BRPI0614485A2 - tetrahydro-1h-pyrido [4, 3, b] substituted indoles as serotonin receptor agonists and antagonists - Google Patents

Abstract

TETRAHYDRO-1 H-PIRIDO [4, 3,] INDOISES REPLACED AS SEROTONIN RECEPTOR AGONISTS AND ANTAGONISTS. The present patent application describes compounds, including all salts, prodrugs, solvates and stereoisomers of the same pharmaceutically acceptable, according to Formula (1), pharmaceutical compositions, which comprise at least one compound according to Formula (1 ) and optionally at least one additional therapeutic agent and treatment processes for various diseases, conditions and disorders associated with the modulation of serotonin receptors, such as, for example: metabolic diseases, which include, but are not limited to obesity, diabetes, diabetic complications, arteriosclerosis, impaired glucose tolerance and dyslipidemia; central nervous system disorders that include, but are not limited to, anxiety, depression, obsessive compulsive disorder, panic disorder, psychosis, schizophrenia, sleep disorders, sexual disorders and social phobias; headache; migraine and gatrointestinal disorders using the compounds according to Formula (1)

Description

Patent Descriptive Report for "TETRAHI-DRO-1H-PYRIDO [4, 3, b] SUBSTITUTED INDONES AS SEROTONIN RECEPTOR AGANISTS".

BACKGROUND

The present invention relates to neurotransmitter / hormones serotonin (5-hydroxytryptamine, 5-HT) regulating many physiological processes through a group of at least 14 distinct receptors which are organized into 7 subfamilies (Hoyer, D. et al., Pharmacol. Rev. 46, 1994). The 5-HT2 family is composed of the 5-HT2A, 5-HT2B and 5-HT2C receptors which are determined by homology and pharmacological properties.

There is a substantial correlation to the connection between 5-HT 2 receptor modulation and a variety of diseases and therapies. Prior to the early 1990s the 5-HT2c and 5-HT2a receptors were referred to as 5-HT1c and 5-HT2, respectively.

Selective or non-selectively direct or indirect 5-HT 2 receptor agonism or antagonism has been associated with the treatment of various central nervous system (CNS) disorders including obesity, depression, schizophrenia and bipolar disorders. In the recent past, the contribution of serotonergic activity to the mode of action of anti-obesity drugs has been well documented. Compounds that increase basalgeral serotonin level in the CNS have been developed as anorectic drugs. Serotonin-releasing agents, such as fenfluramine, function by increasing the amount of serotonin present in the synapsenervosa. These discontinuation treatments, however, are not exempt from side effects. Due to the mechanism of action of serotonin-releasing agents, they affect the activity of a number of serotonin receptor subtypes in a wide variety of organs including those not associated with the desired mechanism of action. This non-specific modulation of the serotonin receptor family most likely plays a significant role in the side effect profile. In addition, these compounds or their metabolites often have a high affinity for a number of serotonin receptors as well as a large number of other monoamine neurotransmitters and nuisance receptors. Removal of part of the receptor cross-reactivity would allow verification and possible development of potent therapeutic ligands with an improved side effect profile.

The 5-HT2c receptor is a G protein-coupled receptor. It is almost exclusively expressed in the central nervous system including the hypothalamus, hippocampus, amygdala, solitary tract nucleus, spinal cord, cortex, bulb olfactory area, ventral tegmental area (VTA), nucleusaccumbens, and choroid plexus (Hoffman, B. and Mezey, E., FEBS Lett., 247,1989). There is ample evidence supporting the function of 5-HT2q receptor selective ligands in a number of disease therapies. Kundockout Knockout for 5-HT2c develops a late-stage obesity syndrome that is not reversed by fenfluramine or other direct acting 5-HT2c agonists such as mCPP (Nonogaki, K. et al., NatureMed., 4, 1998; Vickers, S et al., Psychopharmacology, 143, 1999). Administering selective 5-HT2c agonists to rats causes a reduction in food intake and a corresponding reduction in body weight (Vic-kers, S. et al., Br. J. Pharmacol., 130, 2000) and these responses. may be blocked by administration of selective 5-HT2c antagonists (Vicker, S. et al., Neuropharmacol., 41, 2001). Modulation of the 5-HT2c receptor in the hypothalamus may also influence thermoregylation (Mazzo-la-Pomietto, P et al., Psychopharmacology, 123, 1996), sleep (Sharpley, A. et al., Neuropharmacology, 33, 1994), on sexual behavior and neuroendocrine function (Rittenhouse, P. et al., J. Pharmacol. Exp.Ther., 271, 1994). Activation of 5-HT2C receptors in VTA modulates vaccination of dopaminergic neurons that are involved in depression aspects (Di Matteo, V. et al., Trends Pharmacol. Sci., 22, 2001) and 5-HT2C receptor agonists such as WAY 161503, RO 60-0175 and RO 60-0332 are active in rodent models of depression (Cryan, J. and Lucki, I., J. Pharmacol. Exp. Ther., 295, 2000). 5-HT 2 Agonists have been reported to reduce the satisfactory effects of nicotine administration in rats (Grot-tick, A. et al., Psychopharmacology, 157, 2001) and influence rodent responses to cocaine administration (Grottick, A. et al. J. Pharma-col Exp Ther, 295, 2000). Modulation of 5-HT2c receptors in the spinal cord may influence pain perception (Chojnacka-Wojcikj, et al., Pol. J. Pharmacol., 46, 1994). There is still data indicating that 5-HT2c receptor agonists mCPP and RO 60-0175 mediate penile erections in rats (Millan, M. et al., Eur J. Pharmacol. 325, 1997).

DETAILED DESCRIPTION

The present patent application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally at least one additional therapeutic agent and methods of treating various diseases, health conditions and disorders. associated with modulation of serotonin receptors such as, for example: metabolic disorders, including, but not limited to obesity, diabetes, diabetic complications, atherosclerosis, impaired glucose tolerance, and delipidemia; central nervous system disorders that include, but are not limited to anxiety, depression, obsessive compulsive disorder, panic disorder, psychosis, schizophrenia, sleep disorder, sexual disorder, and social phobias; headache pain; migraine; and gastrointestinal disorders using the compounds according to Formula I

<formula> formula see original document page 4 </formula>

including all pharmaceutically acceptable salt forms, prodrugs, solvates and stereoisomers thereof, wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are described herein.

DEFINITIONS

The following definitions apply to terms that are used throughout this descriptive report, unless otherwise limited in specific cases. Unless otherwise indicated, the term "alkyl" as used herein alone or as part of of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 6 carbons, in the normal chain, such as, for example, methyl, ethyl, propyl, isopropyl, butyl t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof and the like.

The term "alkylene" as used herein alone or as part of another group refers to earlier alkyl linking groups which have single bonds for bonding with other groups on two different carbon atoms.

Unless otherwise indicated, the term "alkenylated" as used herein alone or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 6 normal chain carbons which include one or more normal chain double bonds, such as, for example, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2 -hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl and the like.

The term "alkenylene" and as used herein alone or as part of another group refers to alkenyl bonding groups, which have single bonds for bonding into two carbonodifferent atoms.

Unless otherwise indicated, the term "alkynyl" as used herein alone or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 normal chain carbons, which include one or more normal chain triple bonds, such as, for example, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentinyl, 3-pentinyl, hexinyl, 3-hexinyl, 2-heptinyl, 3-heptinyl, 4-heptinyl, 3-octinyl, 3-noninyl, 4-decinyl, 3-undecinyl, 4-dodecinyl and the like and which may be optionally substituted by one or more functional groups as defined above for alkyl.

The term "alkynylene" as used herein alone or as part of another group refers to alkynyl bonding groups, which have single bonds for bonding into two carbonodifferent atoms.

The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine and iodine.

Unless otherwise indicated, the term "cycloalkyl" as used herein alone or as part of another group refers to saturated or partially saturated cyclic hydrocarbon groups (containing 1 or 2 double bonds) containing 1 to 2 3 rings, including monocyclic alkyl, bicyclic alkyl and tricyclic alkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons, forming the ring such as, for example, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

<figure> figure see original document page 6 </figure>

wherein the cycloalkyl may be fused to 1 aromatic ring as described for aryl.

The term "heterocyclyl" as used herein refers to an unsubstituted or substituted stable 4-, 5-, 6- or 7-membered monocyclic ring system which may be saturated or unsaturated and consisting of carbon atoms and from one to four heteroatoms selected from the group N, O, S, SO and / or SO2, where nitrogen heteroatoms may be optionally oxidized and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached to any heteroatom or carbon atom that results in the creation of a stable structure such as, for example, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl and oxadiazolyl. The term "aryl" as used herein alone or as a moiety with another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring part such as, for example, phenyl or naphthyl and may optionally include one to three additional "aryl" fused rings such as, for example, aryl, cycloalkyl ring heteroaryl-Ia or cycloheteroalkyl.

The term "heteroaryl" as used herein refers to a 5-, 6- or 7-membered aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, sulfur, oxygen and / or a SO or SO 2 group. Such rings may be fused to another ring such as, for example, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl and include possible N-oxides.

The term "oxy" as used herein as part of another group refers to an oxygen atom that serves as a linker between two groups such as, for example, hydroxy, oxyalkyl, oxyalkenyl, oxykynyl, oxy-perfluoroalkyl, oxyaryl, oxiheteroarila, oxicarboalquila, oxicarboalquenila, oxicarboalquinila, oxicarboarila, oxicarboheteroarila, oxicarbocicloalquila, oxicarboaminoalquila, oxicarboaminoalquenila, oxicarboaminoalquinila, oxy-carboaminoarila, oxicarboaminocicloalquila, oxicarboaminoheterociclila, oxy-carboaminoheteroarila, aminocarboxialquila, aminocarboxialquenila, amino carboxialquinila, aminocarboxiarila, aminocarboxicicloalquila, aminocarboxylic - and heterocyclyl aminocarboxiheteroarila .

The term "carbo" as used herein as part of another group refers to a carbonyl group (C = O) which serves as a linker between two groups such as, for example, carboxyalkyl, carboxyalkenyl, carboxyalkyl, carboxyaryl, carboxyheteroaryl, carboxycycloalkyl, oxycarb -boalquila, oxicarboalquenila, oxicarboalquinila, oxicarboarila, oxicarbohete-roarila, oxicarbocicloalquila, carboaminoalquila, carboaminoalquenila, carbo-aminoalquinila, carboaminoarila, carboaminocicloalquila, carboheterociclila, carboheteroarila, carboaminoheterociclila, carboaminoheteroarila, aminocar-boalquila, aminocarboalquenila, aminocarboalquinila, aminocarboarila, amino-nocarbocicloalquila, aminocarboheterociclila , aminocarboheteroaryl, oxycarboaminoalkyl, oxycarboaminoalkenyl, oxycarboaminoalkynyl, oxicarbonaminoalkyl, oxycarboaminocycloalkyl, oxycarboaminoheterocyclyl, oxycarbonaminoalkyl, aminocarboxykycarinyl, aminocarboxylaminoalkyl, aminocarboxylaminoalkyl oxycycloalkyl, aminocarboxyheterocyclyl, aminocarboxyheteroaryl, aminocarboaminoalkyl, aminocarboaminoalkenyl, aminocarboaminoalkyl, aminocarboamocycloalkyl, aminocarboheterocyclyl, aminocarheteroaryl aminocarheteroaryl, aminocarboaminoalkyl, aminocarboxymethylcarinyl aminocarboxymethyl aminocarboxymethyl aminocarboxylamino

The term "thio" as used herein as part of another group refers to a sulfur atom which serves as a ligand between two groups such as, for example, thioalkyl, thioalkenyl, thioalkylyl, thioaryl, thioheteroaryl, thocycloalkyl and thioheterocyclyl.

The term "perfluor" as used herein as part of another group refers to a group wherein more than one hydrogen atom attached to one or more carbon atoms in the group has been replaced by a defluor atom such as, for example, perfluoroalkyl, perfluoroalkenyl perfluoroalkynyl and oxiperfluoroalkyl.

The term "amino" as used herein alone or as part of another group refers to a nitrogen atom which may be terminal or a ligand between two other groups, wherein the group may be a primary, secondary or secondary amine. (two hydrogen atoms attached to the nitrogen atom, one hydrogen atom attached to the nitrogen atom, and no hydrogen atoms attached to the nitrogen atom, respectively) such as, for example, amino, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl , aminoheteroarila, aminocicloalquila, alkylamino, alque-propionylamino, alkynylamino, arylamino, heteroarylamino, cycloalkylamino, carboa-minoalquila, carboaminoalquenila, carboaminoaquiinila, carboaminoarila, carboaminocicloalquila, carboheterociclila, carboheteroarila, carboaminohe-terociclila, carboaminoheteroarila, aminocarboalquila, aminocarboalquenila, aminocarboalquinila, aminocarboarila, aminocarbocicloalquila , aminocarboheterocyclyl, aminocarboheteroari la, oxicarboaminoalquila, oxicarboaminoal-quenila, oxicarboaminoalquinila, oxicarboaminoarila, oxicarboaminocicloal-quila, oxicarboaminoheterociclila, oxicarboaminoheteroarila, aminocarboxial-quila, aminocarboxialquenila, aminocarboxialquinila, aminocarboxiarila, aml · nocarboxicicloalquila, aminocarboxiheterociclila, aminocarboxiheteroarila, aminocarboaminoalquila, aminocarboaminoalquenila, aminocarboaminoal-quinila, aminocarboaminoarila, aminocarboaminocicloalquila, aminocarbohe-terociclila, aminocarboheteroarila, aminocarboaminoheterociclila, aminocar-boaminoheteroarila, aminossulfoalquila, aminossulfoalquenila, aminossulfo-alkynyl, aminossulfoarila, aminossulfocicloalquila, aminossulfoheterociclila, aminossulfoheteroarila, aminossulfoalquilamino, aminossulfoalquenilamino, aminossulfoalquinilamino, aminossulfoarilamino, aminossulfocicloalquilami it, and aminossulfoheterociclilamino aminossulfoheteroarilamino.

The term "nitrile" as used herein refers to a cyano group (a triple bond carbon atom to a nitrogen atom).

The term "sulfinyl" as used herein as part of another group refers to a group -SO- such as, for example, sulfinylalkyl, sulfinylalkynyl, sulfinylaryl, sulfinylcycloalkyl, sulfinylheterocyclyl, sulfinylheteroaryl, sulfinylamino and sulfinylamino.

The term "sulfonium" as used herein as part of another group refers to a group -SO 2 - such as, for example, sulfonylalkyl, sulfonylalkenyl, sulfonylalkynyl, sulfonylaryl, sulfonylcycloalkyl, sulfonyl-rocyclyl and sulfonyleteroaryl.

Administration of a patent application therapeutic agent includes administration of a therapeutically effective amount of the patent application agent. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent for treating or preventing a health condition that can be treated by administering a composition of the patent application. Such amount is sufficient to exhibit a detectable or predictive therapeutic or improvement effect. The effect may include, for example, treatment or prevention of the health conditions listed herein. The precise amount of efficiency required for an individual will depend on the size and health of the individual, the nature and extent of the health being treated, the recommendations of the treating physician and the therapeutic agents or the combination of selected therapeutic agents for administration. -dog. Thus, it is not useful to specify an exact accurate early amount.

Any compound that can be converted in vivo to provide the bioactive agent (i.e. the compound of formula I) is a prodrug within the scope and spirit of the patent application.

The term "prodrug esters" as used herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula I with alkyl, alkoxy or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonoates, benzoates and the like.

Various forms of prodrugs are well known in the art and are described in:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch. 31, (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);

c) The Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., Chap. 5, pp. 113-191 (Harwood AcademicPublishers, 1991).

Said references are incorporated herein by reference. All stereoisomers of the compounds of the present application are considered, either in admixture or in pure or substantially pure form. The compounds of the present patent application may be asymmetric centers at any of the carbon atoms including any of the R substituents. Accordingly, the compounds of formula I may exist in enantiomeric or diastereomeric forms or mixtures thereof. Processes for the preparation may use pharmaceutics, enantiomers or diastereoisomers as starting materials. When diastereoisomeric or enanciomeric products are prepared, they may be prepared by conventional methods, for example chromatographic techniques or fractional crystallization.

Acceptable pharmaceuticamerite salts of the compounds of formula I of the patent application include alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabiethylamine as well as pharmaceutically acceptable anions such as chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutara-to , stearate and naturally occurring amino acid salts such as arginine, lysine, lanline and the like and prodrug esters thereof.

SYNTHESIS

Throughout this patent application, the following abbreviations are used with the following meanings:

Reagents:

Et3N triethylamine

TFA trifluoroacetic acid

NBS N-Bromosuccinimide

LAH Lithium Aluminum Hydride

BINAP 2,2'-bis (diphenylphosphino) -1,1'-binaphthalene

DEAD diethylazodicarboxylate

Pd2dba3 Tris (dibenzylideneacetone) dipaladium (O)

Pd (dppf) CI2 [1,1'-bis (diphenylphosphino) ferrocene] dichloro-palladium (ll)

Solvents:

THF tetrahydrofuranMeOH methanolEtOH ethanolEtOAc ethyl acetateHOAc acetic acid DMF dimethyl formamideDMSO dimethyl sulfoxideDME dimethoxyethaneEt2O diethyletherIPA isopropanolOthers: ArylPh phenylMe ethyl EthylRMNbutylbenzylcarbonylbenzylcarbonyl propyl benzylcarbonylbenzylcarbonylbenzylcarbonate catai lticomL millilitronM nanometerppm part per millionpsi per inch squaredammol millimolmg milligrammag gramkg kilogramTLC thin layer chromatographyHPLC high pressure liquid chromatographyort ambient temperatureq. watery saturadopg protective group

The compounds of the present patent application may be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present application may be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereof as considered by those skilled in the art. Preferred methods include, but are not limited to those described below. All references cited herein are incorporated herein in their entirety by reference herein.

The novel compounds of this patent application may be prepared using the reactions and techniques described in this section. Reactions are carried out in solvents suitable for the reagent and the materials employed and are suitable for the transformations to be performed. In the description of the synthesis methods described below, it should be understood that all proposed reaction conditions including The choice of solvent, the reaction atmosphere, the reaction temperature, the duration of the experiment and the processing procedures are chosen as the standard conditions for such reaction, which should be easily recognized by one of skill in the art. It is understood by one skilled in the art of organic synthesis that the functionality present in various parts of the molecule must be compatible with the proposed reagents and reactions. Such restrictions on substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods must then be used.

The preparation of the compounds of Formula (I) of the present application may be carried out in a convergent or sequential synthetic manner. Detailed synthetic preparations of the compounds of Formula (I) are shown in the following reaction schemes. The skill required in the preparation and purification of the compounds of Formula (I) and the intermediates leading to these compounds is well known to those skilled in the art. Purification procedures include, but are not limited to normal or reverse phase chromatography. , crystallization and distillation.

Various methods for preparing the compounds of the present patent application are illustrated in the schemes and examples shown below. Substitutions are as described and defined above.

The compounds of Formula (I) of this patent application may be prepared as shown in Scheme 1. Thus, preparation of an aryl hydrazine (II) is carried out, for example, by treatment of a corresponding substituted ananiline with NaNO 2 followed by reduction of the compound. N-nitrous termediary with LAH or SnCl2 in conc. HCI. The indolcentral (I) assembly is performed by Fischer's indole cyclization of aryl hydrazine and a suitably substituted ketone [i.e. (III)] by methods described by, but not limited to RJ Sundberg, "Indoles, Best Synthetic Methods" 1996, Academic Press, San Diego, CA. For example, treatment of aryl hydrazine (II) as the free base or the corresponding mineral acid salt with ketone (III) (R1 = H, Bn, CBZ, CO2 Etc) in an alcoholic solvent in the presence of mineral acid directly supplies the indoles (I). Alternatively, indoles (I) may be constructed in steps by formation of intermediate hydrazones (IV) under a neutral condition followed by rearrangement under an acidic condition.

Scheme 1

<formula> formula see original document page 14 </formula>

Heat

The compounds of Formula (II) may be prepared as described in Scheme 2. Formation of aryl amine (VI) may be accomplished by reducing the corresponding aryl nitro compound (V). Reduction can be performed with a variety of reducing agents, for example LAH1SnCl2, NaBH4, N2H4, etc. or with hydrogen in the presence of a suitable catalyst such as Pd (O) in carbon or platinum oxide etc., (see Hudlicky, M., "Reductions in Organic Chemistry", Ellis Horwood, Ltd., Chichester, UK). , 1984). Aryl hydrazine (II) formation can then be performed as described above in Scheme 1 or more directly by treating the aniline (VI) with HCl aq., SnCl2 and NaNO2 at room temperature (see, Buck, JS, Ide, WS , Org. Sin., Coll. Vol., 2, 1943, 130). This latter procedure is especially important when initiating synthesis with halogenated aryl amines (VI). The need for the preparation of the hydrazine intermediate without the use of strong reducing conditions is critical in these examples.

SCHEME 2

Another route related to the hydrazines of Formula (II) is shown in Scheme 3. When an aromatic substitution pattern containing a portion of sulfur or oxygen is desired, the following route may be employed. Displacement of a halogen (Cl, F) from a suitably substituted aryl nitro derivative (VII) by the prerequisite nucleophile under basic conditions provides type (VIII) intermediates. Reduction of the nitro portion followed by elaboration of the resulting amine into substituted or unsubstituted hydrazine (IX) is as described above. This approach of initiating synthesis with a nitrobenzene derivative such as (VII) is responsible for a variety of derivatization. Higher substituted nitrobenzenes can be obtained by traditional synthetic manipulation (i.e. aromatic substitution) and are known to those skilled in the art (see Larock, R.C., Comprehensive Organic Transformations, VCHPublishers, New York, 1989).

<formula> formula see original document page 16 </formula>

An alternative approach for the introduction of various substituents R1 and R3 is shown in Scheme 4. Fischer's indole cyclization of da1α-aryl hydrazine (X) with piperidone (XI) as described above provides indole ( XII). Carboline nitrogen is then protected with a suitable protecting group (i.e. Pg = Boc, Bn, CBZ, CO2R) as described in Greene, TW, Wuts, PGW, "Protective Groups in Organic Synthesis, 2-Edition", John Wiley and Sons, Inc., New York, pages 309-405, 1991. Alkylation of indole nitrogen under basic conditions provides intermediate (XIII). The protecting group is then removed under a variety of conditions to regenerate the basic amine which can be alkylated by treatment with a suitably substituted alkyl halide (R 1 Cl, R 1 Br or R 11) and a base as described, for example, by Glennon, RA and others, Med. Chem. Res., 1996, 197 to provide the differently substituted selective indoles (I).

Scheme 4

<formula> formula see original document page 16 </formula>

Fischer's indole cyclizations using unsubstituted phenyl hydrazines at both 2 'and 6' positions often result in a mixture of regio-isomeric indoles. Scheme 5 shows an approach for the synthesis of regio-specific indoles. Fischerde's indole cyclization a suitably substituted 2-bromo-phenyl hydrazine (XIV) and a pi-peridone (XI) yields the R4-bromoindole (XV) exclusively The R4-bromo substituent may then be removed by hydrogenation in the presence of a catalyst such as as Pd (0) / C in a suitable solvent such as MeOH, EtOH or the like to provide (XVI) Various substitutions of R1 and R3 as described in Scheme 4 provide indole (XVII).

SCHEME 5

<formula> formula see original document page 17 </formula>

The preparation of compounds of Formula (I) with additional defunctional diversity in the aromatic ring of the tricycle may be accomplished using activating groups such as bromide, iodide, triflates and / or diazo derivatives is described herein. These activated aryl derivatives (XVIII) can serve as excellent counterparts to a number of important synthetic transformations and can be readily obtained through the synthesis sequence exemplified in Scheme 1, Scheme 4 and Scheme 5. As shown in Scheme 6, treatment of activated indoles (XVIII) with an appropriate alkyl zinc reagent (XIX) in the presence of the Pd (O) catalyst such as Pd (dppf) CI2> Pd2 (dba) 3, Pd (PPh3) 4 orPd (PPh3) 2CI2 and or without a copper salt (1), provides the derivatives (I) wherein R 4 is a variety of alkyl group (see Knochel, P. et al. Chem., 1993, 93, 2117; and Weichert. A. et al. Sin. Lett. 1996, 473). Protection of amine functionality must be carried out if R1 = H (see Greene and others for amine protections). This is easily accomplished, for example, by treating indole derivatives (XVIII) with an excess of (Boc) 2O in aq. and dioxane. This approach allows the introduction of a variety of alkyl substituents at the position of the reactivation group at the late stage of the syntheses.

In addition, there is a wide range of procedures and protocols for the functionalization of haloaromatic compounds, arylthiazonium and dearyltriflate. These procedures are well known in the art and described, for example (see Stanforth, SP, Tetrahedron, 1998, 263; Buchwald, SL et al., J. Am. Chem. Soc., 1998, 9722; StiHej JK et al., J. Am. Chem. Soc., 1984, 7500). These procedures include biaryl couplings, alkylations, acylations, amination and amidation. The power of the functionalization of palladium-catalyzed aromatic centers has been fully explored in the last decade. An excellent review of this field can be found in J.Tsuji, "Palladium Reagents and Catalysts, Innovations in Organic Synthesis", J. Wiley and Sons, New York, 1995.

SCHEME6

<formula> formula see original document page 18 </formula>

Ra = Br, I, OTf, N2

Similarly, the above coupling protocol can be applied to indole derivatives (XX) containing activating groups at alternate positions as shown in Scheme 7. These indole derivatives (XX) could still be readily obtained by the sequence of synthesized in Scheme 1 and Scheme 4 through the use of properly functionalized phenylhydrazines. Subsequent coupling with a variety of alkyl zinc reagents (XXI) may be performed as described above in Scheme 6 to provide alkylindole adducts (XXII). This protocol is also treatable to bromide, iodine to, triflates and / or diazo derivatives of R6 and R7.

<formula> formula see original document page 19 </formula>

Additional methods of preparing differentially substituted analogues are shown in Scheme 8 and proceed from bromine or iodine derivatives (XVIII). Treatment of indole (XVIII) derivatives with diphenylmethyl imine in the presence of a Pd (O) catalyst such as Pd2 (dba) 3, Pd (PPh3) 4 or Pd (PPh3) 2Cl2 and a suitable ligand such as Bl-NAP or PPh3 and a base such as NaOtBu or CsCO3 in a suitable solvent such as DMF1 toluene, THF1 DME or the like provide an imine intermediate. Basic hydrolysis (hydroxylamine and sodium acetate in methanol) provides the primary aniline derivative (XXIII). Activated indole (XVIII) may also react with a suitable base such as n-BuLi or t-BuLi followed by the addition of B (O-Pr) 3 in a suitable solvent such as THFfDME or the like and provide the ester intermediate. boronic aryl. Intermediate treatment with a suitable acid such as HOAc followed by oxidation with H2 O gives the phenol derivatives (XXIV). Similarly, indole derivatives (XVIII) can be converted to thiophenol derivatives (XXV) by treatment with a suitable base such as n-BuLi or t-BuLi followed by the addition of sulfur in a suitable solvent such as comopentane, hexane, THF, DME or the like followed by aqueous processing In analogy to Scheme 7, the protocol described in Scheme 8 may also be applied to analogs of (XX) wherein the groups R5, R6 or R7 are Br or I to provide analogues of (XXIII), (XXIV) or (XXV) wherein the amino, hydroxy or thiol group is in position R5, R6 or R7.

<formula> formula see original document page 20 </formula>

These newly formed aniline, phenol and thiophenol functionalities can also be used as excellent counterparts for a number of important synthetic transformations. Several examples are described in Scheme 9. For example, aniline (XXIII) may be reacted with an appropriate aldehyde in the presence of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride under mild reaction conditions, such as in the presence of acetic acid, in a solvent and dequate such as 1,2-dichloroethane, THF, methanol or acetonitrile to produce the variety of aniline secondary analogs (XXVI). Aniline (XXII-I) may also be reacted with 1 equivalent of various alkylketides or alkylsulfonates in the presence of a suitable base such as NaH, K2CO3, Na2CO3, CsCO3, Et3N or Et2 (I-Pr) N in a suitable solvent such as such as DMF, DMSO, toluene, THF, DME or the like, produce a variety of aniline secondary analogs (XXVI). Similarly, the coupling of phenols (XXIV) with various alkyl halides or alkylsulfonates in the presence of a suitable base such as NaH or KOH in a suitable solvent such as DMF, DMSO, toluene, THF, DME or the like yields alkoxy indoline (XXVI-I) . Alternatively, the various alkyl alcohols couple with the phenols (XXIV) under the Mitsunobu reaction condition (See Mitsunobu, O. Sinthesis1981, 1-28) in the presence of DEAD with a suitable ligand such as PPh3or Et3P in a suitable solvent such as as THF to provide the alkoxy Indine (XXVII). Finally, the various alkylketides or alkylsulfonates may also be coupled with thiophenol (XXV) in the presence of a base such as K2CO3, Na2CO3, NaH or KOH in a suitable solvent such as DMF1 DMSO, toluene, THF1 DME or the like. sulfide derivatives (XXVIII). In analogy to Scheme 7, the protocol described in Scheme 9 may also be applied to analogues of (XXIII), (XXIV) or (XXV) wherein the R51, R6 or R7 groups are NH2, OH or SH to provide the analogs of (XXVI), (XXVII) or (XXVIII), respectively.

SCHEME 9

<formula> formula see original document page 21 </formula>

One method for the preparation of biaryl anilines (XXX) is described in Scheme 10 and proceeds from the aniline derivatives (XXIII). Aryl bromide (XXIX) treatment in the presence of a Pd (O) catalyst such as Pd2 (dba) 3, Pd (PPh3) 4 or Pd (PPh3) 2Cl2 and a suitable ligand such as BINAP or PPh3 and a Base such as NaOffiu or CsCO3 in a suitable solvent such as DMF, toluene, THF, DME or the like provides asbiaryl anilines (XXX). In analogy to Scheme 7, the protocol described in Scheme 10 may also be applied to analogues of (XXIII) wherein R5, R6 or R7 are NH2 to provide analogs of (XXX) wherein the arylamino group is in position R5, R6 or R7. SCHEME 10

<formula> formula see original document page 22 </formula>

In addition, phenols (XXIV) also react with a functionalized arylboronic acid (XXXI) in the presence of Cu (II) 1 species such as Cu (OAc) 2 or CuF6 (MeCN) 4 and a base such as NEt3 or K2CO3 in a Suitable solvent such as CH 2 Cl 2 to provide aryloxy indoline (XXXV) as shown in Scheme 11. In analogy to Scheme 7, the protocol described in Scheme 11 may also be applied to analogs of (XXX) where the group R5, R6 or R7 is OH to provide the analogues of (XXXII) or wherein the aryloxy group is in the R5, R6 or R7 position.

SCHEME 11

<formula> formula see original document page 22 </formula>

It is understood that the compounds of the present patent application may be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present patent application may be synthesized using the methods described herein, together with the synthetic methods known in the art of synthetic organic chemistry, as described by those skilled in the art.

UTILITIES AND COMBINATIONS

Utilities

The compounds of the present patent application are 5HT modulators and include compounds which are, for example, selective agonists, partial α-agonists, antagonists or partial antagonists of the 5HT2c receptor. Accordingly, the compounds of the present patent application may be useful for the treatment or for the prevention of diseases and disorders associated with 5HT receptor activity. Preferably, the compounds of the present application have activity as 5HT2c receptor agonists and may be used in the treatment of diseases or disorders associated with 5HT2c receptor activity.

Accordingly, the compounds of the present patent application may be administered for the treatment of a variety of health conditions and diseases, including, but not limited to, metabolic and nutritional disorders as well as health conditions associated with metabolic disorders (e.g. , obesity, diabetes, arteriosclerosis, hypertension, polycystic ovarian disease, cardiovascular disease, osteoarthritis, dermatological disorders, impaired glucose hemostasis, insulin resistance, hypercholesterolemia, hypertriglyceridemia, sleep disorders, delipidemic health status, bulimia nervous and eating disorders); pain; sleep disorders and psychiatric disorders, such as substance abuse, depression, anxiety, psychosis, mania and schizophrenia.

These compounds could also be used to improve cognitive function (for example, the treatment of dementia including Alzheimer's disease, short-term memory loss and attention deficit disorders); neurodegenerative disorders (eg, Parkinson's disease, cerebral stroke and head injury) and hypotension (eg endotoxin-induced hemorrhagic hypotension). These compounds could also be used for the treatment of cardiac dysfunction (e.g., associated with valve disease, myocardial infarction, cardiac hypertrophy or congestive heart failure); and for the improvement of the general pulmonary function; transplant rejection; rheumatoid arthritis; osteoarthritis; fibromyalgia; multiple sclerosis; inflammatory bowel disease; lupus; graft disease vs. host; T cell-mediated hypersensitivity disease; psoriasis; asthma; Hashimoto's thyroiditis; Guillain-Barre syndrome; cancer; contact dermatitis; allergic rhinitis; and ischemic or reperfusion damage. These compounds could also be used for the treatment of sexual dysfunction and erectogenesis.

Compounds useful in the treatment of appetite or motivational disorders regulate cravings to consume sugars, carbohydrates, alcohol or drugs and more generally to regulate consumption with hedonic value. In the present description and claims, appetite disorders are understood to mean: disorders associated with a substance and especially substance abuse and / or substance dependence, eating behavior disorders, especially those likely to cause overweight, regardless of their origin, for example: bulimia nervosa, craving for sugars. The present patent application further therefore relates to the use of a 5HT2C receptor agonist for the treatment of bulimia and obesity, including obesity associated with type II diabetes (non-insulin dependent diabetes) or more generally. any disease that results in the patient becoming overweight. This may be due to any cause, whether genetic or environmental, including overfeeding and bulimia, polycystic ovary disease, craniopharyngoma, Prader-Willi syndrome, Frohlich syndrome, Type II diabetes, growth hormone deficiency, of Turner and other pathological conditions characterized by reduced metabolic activity or reduced energy expenditure. As used with reference to the utilities described herein, the term "treating" or "treatment" encompasses prevention, partial relief or cure of the disease or disorder. Furthermore, obesity treatment is expected to prevent the progression of medical co-variations of obesity such as arteriosclerosis, Type II diabetes, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, resistance. insulin, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders.

The compounds in the present patent application may further be useful in the treatment of substance abuse disorders, including substance dependence or abuse without physiological dependence. Substances of abuse include alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine (or compounds similar to phencyclidine), sedative or benzodiazepine hypnotics and other (or unknown) substances and combinations of the above. The terms "substance abuse disorders" also include drug, nicotine or alcohol elimination syndromes, and substance-induced anxiety or mood disorder that begins during elimination.

The compounds in the present application may be useful in the treatment of memory impairment and cognitive disturbances. The condition of decreased memory capacity is manifested by decreased ability to learn new information and / or the ability to recall previously learned information. Decreased memory capacity is a primary symptom of dementia and may also be a symptom associated with diseases such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, attention deficit hyperactivity disorder, HIV, cardiovascular disease such as ischemia or stroke, and age-related cognitive decline. Dementias are diseases that include memory loss and additional intellectual damage separate from memory. 5HT2c modulators may also be useful in treating cognitive impairment related to attention-deficit deficits, such as attention-deficit hyperactivity disorder.

The compounds in the present application may also be useful in the treatment of diseases associated with dysfunction of brain dopaminergic systems, such as Parkinson's disease and substance abuse disorders. Parkinsons Disease is a neurodegenerative movement disorder characterized by bradykinesia and tremor.

Combinations

The present patent application includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically efficient amount of at least one of the compounds of formula I, alone or in combination with a pharmaceutical carrier or diluent. Optionally, the compounds of the present application may be used alone, in combination with other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-obesity agents; antidiabetic agents, appetite suppressants; cholesterol / lipid lowering agents, cognition enhancing agents, agents used to treat neurodegeneration, agents used to treat respiratory health, agents used to treat bowel disorders, anti-inflammatory agents; anti-aging agents; antidepressants; antipsychotic agents; sedatives; hypnotics; antihypertensive agents; antitumor and analgesic agents.

Such other therapeutic agent (s) may be administered before, simultaneously with or after administration of 5HT2c modulators according to the patent application.

Examples of suitable anti-obesity agents for use in combination with the compounds of the present application include leptin and leptin sensitizing agents, curtain melano receptor (MC4R) agonists, agouti-related peptide antagonists (AGRP), melanin concentration hormone receptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR) antagonists, orexin antagonists, CCK agonists, GLP-1 agonists, NPY1 or NPY5 antagonists, modulators of NPY2, corticotropin-releasing factor agonists, receptor-3 modulators. (H3), aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, beta 3 adrenergic agonists such as AJ9677 (Takeda / Dainippon), L750355 (Merck) or CP331648 (Pfizer) or other beta 3 agonists which are described in US Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983, and 5,488,064, a thyroid receptor beta modulator such as the thyroid receptor as described in WO 97/21993 (U. Cal. SF), WO99 / 00353 (KaroBio) and WO 00/039077 (KaroBio), a lipase inhibitor such as orlistat or ATL-962 (Alizyme), leptinergics, daadiponectin modulating agents, cannabinoid-1 receptor antagonists such as such as SR-141716 (Sanofi) or SLV-319 (Solvay), acetyl CoA carboxylase (ACC) inhibitors as described in International patent application WO 03/072197 reuptake inhibitors or monoamine release agents such as fenfenfluramine, dexfenfluramine, fluvoxamine , fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, chlortermin, p icilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or mazindol, anorectic agents such as thiopiramate (Johnson & Johnson), axoquine (Regeneron).

Examples of suitable antidiabetic agents for use in combination with the compounds of the present application include: in-suline, which may include short or long lasting forms as well as oral and inhaled forms, insulin secretagogues or insulin sensitizers. , which may include biguanidases, sulfonyl ureas, glycoside inhibitors, aldose reductase inhibitors, PPAR γ agonists such as thiazolidinedones, PPAR α agonists (such as fibric acid derivatives), PPAR δ antagonists or agonists, dual PPAR αJy agonists such as muragytize described in Bristol-Myers Squibb US Patent No. 6,414,002, dipeptidyl peptidase IV (DPP4) inhibitors such as saxagliptin described in US Patent Nos. 6,395,767 and 6,573 287 of Bristol-Myers Squibb, SGLT2 inhibitors such as the compounds described in Bristol-Myers Squibb U.S. Patent Nos. 6,414,126 and 6,515,117, glycogen phosphorylase inhibitors and / or glycitinides as well as glucagon-like peptide receptor agonist and / or agonist and / or a PTP-1B (protein tyrosine phosphatase-1B inhibitor) inhibitor.

The antidiabetic agent may be glucokinase inhibitors, 11 β HSD inhibitors or oral antihyperglycemic agents, which are preferably a biguanide such as metformin or phenformine or salts thereof, preferably metformin HCI. When the antidiabetic agent is a biguanide, the compounds of the present patent application will be employed in a weight to biguanide ratio within the range of from about 0.001: 1 to about 10: 1, preferably from about 0, 01: 1 to about 5: 1.

The antidiabetic agent may also preferably be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (described in US Patent No. 4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other channel acting antihyperglycemic agents. be-ta cell ATP-dependent, with glyburide and glipizide being preferred, which may be administered on the same or in separate oral dosage forms. The oral antidiabetic agent may also be a glycosidase inhibitor such as acarbose (disclosed in US Patent No. 4,904,769) or miglitol (described in US Patent 4,639,436), which may be administered in the same or in forms. separate oral toes.

The compounds of the present patent application may be employed in combination with a PPARγ agonist such as an oral thiazolidinedione agent and antidiabetic agent or other insulin sensitizers (which have an insulin sensitivity effect in NIDDM patients) such as troglitazone (REZULIN of Warner-Lambert, described in US Patent No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi MCC-555 (described in US Patent No. 5,594,016), GL-262570 of Glaxo-Wellcome, englitazone (CP -68722, Pfizer) or darglitazone (CP-86325, Pfizer), isaglitazone (MIT / J & J), JTT-501 (JPNT / P & U), L-895645 (Merck), R-119702 (Sankyo / WL), NN-2344 ('Dr. Reddy / NN) or YM-440 (Yamanouchi) 1 preferably rosiglitazone and pioglitazone.

The compounds of the present patent application may be employed in combination with antihyperlipidemia agents or agents used to treat arteriosclerosis. An example of a hypolipidemic agent would be an HMG CoA reductase inhibitor that includes, but is not limited to, amevastatin and related compounds as described in US Patent No. 23,983,140, Iovastatin (mevinolin) and related compounds as descripone US Patent No. 4,231,938, pravastatin and related compounds as described in US Patent No. 4,346,227, simvastatin and related compounds as described in US Patent Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may be employed herein include but are not limited to fluvastatin, disclosed in US Patent No. 5,354,772, cerivastatin described in US Patent Nos. 5,006,530 and 5,177,080, atorvastatin described in U.S. Patent Nos. 4,681,893.5273,955, 5,385,929 β 5,686,104, pitavastatin (Nis-san / Sankyo nisvastatin (NK-104) or itavastatin), disclosed in US Patent No. 5,011,930, Shionogin rosuvastatin Astra / Zeneca (visastatin (ZD-4522)) described in US Patent No. 5,260,440 and related statin compounds described in US Patent No. 5,753,675.

Squalene synthetase inhibitors suitable for use herein include, but are not limited to, α-phosphono sulfonates described in US Patent No. 5,712,396, those described by Biller et al., J. Med. Chem., 1988, Vol. 31 No. 10, pp 1869-1871, including deisoprenoid (fosfinylmethyl) phosphonates as well as other known inhibitors of squalene are, for example, as described in U.S. Patent Nos. 4,871,721 and 4,924,024e in Biller, SA, Neuenschwander, K., Ponpipom, MM and Poulter, C.D., Current Pharmaceutical Design, 2, 1-40 (1996).

In addition, other suitable squalene synthetase inhibitors for use herein include the terpenoid pyrophosphates described by P. Ortizde Montellano et al., J. Med. Chem., 1977, 20: 243-249, the farnesyl dodiphosphate analogue A and presqualene pyrophosphate (PSQ-PP) as described by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, the phosphinylphosphonates reported by McCIard1 R.W. et al., J.A.C.S., 1987, 109: 5544, the cyclopropanes reported by Capson, T.L., PhD dissertation, June 1987, Dept. Med. Chem. U of Utah, Summary, Table of Contents, pp 16, 17, 40-43, 48-51, Summary, pyrrolidine derivatives as described by Sasyou et al., WO 02/083636 and cyclic amine derivatives substituted by N-aryl described by Okada et al., WO 02/076973.

Other suitable hypolipidemic agents for use herein include, but are not limited to, fibrous acid derivatives, αPPAR agonists such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol and related compounds as described in US Patent No. 2 3,674,836, probucol, phenylfibrate and gemfibrozil being preferred, bile acid sequestering agents such as cholestyramine, colestipole DEAE-Sephadex (SECOLEX, POLICEXIDE) and colestagel (Sankyo / Geltex), as well as Iipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanamine lamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), is-tigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative) ), melinamide (Sumitomo) 1 Sandoz58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylic acid, aspi poly (diallyl methylamine) derivatives such as those described in US Patent No. 4,759,923, quaternary amine polyl (diallyldimethylammonium chloride) and ionenes such as those described in US Patent No. 4,027,009 and other cholesterol lowering agents in known serum.

The other hypolipidemic agent may be an ACAT inhibitor (which also has anti-atherosclerosis activity) as described in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area inhalers", Nicolosi et al., Atherosclerosis (Shannon, Irei). (1998), 137 (1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoBI O-containing lipoprotein", Ghiselli, Giancarlo1Cardiovasc. Drug Rev. (1998), 16 (1), 16-30; "RP 73163: A bioavailable alkyl sulfinyl diphenylimidazole ACAT inhibitor", Smith, C. et al., Bioorg. Med.Chem. Lett. (1996), 6 (1), 47-50; "ACAT inhibitors: physiologic mechanismsfor hypolipidemic and anti-atherosclerotic activities in experimental animals," Krause et al., Editor (s): Ruffolo, Robert R., Jr .; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla .; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovice others, Curr. Med. Chem. (1994), 1 (3), 204-25; "Inhibitors of acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocolesterolemic agents. 6.The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA: cholesterol acyltransferase (ACAT). 7. Development of a seriesof substituted N-phenyl-N '- [(1-phenylcyclopentyl) methyl] ureas with enhancedhypocolesterolemic activity ", Stout et al., Chemtracts: Org. Chem. (1995), 8 (6), 359-62 or TS-962 (Taisho Pharmaceutical Co. Ltd.), as well as F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8. -434.

The hypolipidemic agent may be a regulator for more LDL receptor activity such as MD-700 (Taisho Pharmaceutical Co.Ltd) and LY295427 (Eli Lilly). The hypolipidemic agent may be a cholesterol absorption inhibitor, preferably Schering-Plow SCH48461 (ezetimibe) as described in Atherosclerosis 115, 45-63 (1995) eJ. Med. Chem. 41,973 (1998).

The other lipid agent or lipid modulating agent may be a cholesteryl transfer protein (CETP) inhibitor such as Pfizer's Torcetrapib® as described in W0 / 0038722 and EP818448 (Bayer) and EP 992496 and SC-744 and SC -795 from Pharmacia, as well as CETi-1 and JTT-705.

The hypolipidemic agent may be an inhibitor of the Na + / bile acid ileum co-transporter as described in Drugs of theFuture, 24, 425-430 (1999). The ATP citrate lyase inhibitor which may be employed in combination with the patent application may include, for example, those described in U.S. Patent No. 5,447,954.

The other lipid agent further includes a phytoestrogen compound as described in WO 00/30665 including isolated soy protein, soy protein concentrate or soy flour as well as an iso-flavone such as genistein, daidzein glycitein or equol or phytosterols, fi-tostanol or tocotrienol as described in WO 2000/015201; a beta-lactam cholesterol absorption inhibitor as described in EP 675714; an HDL up-regulator such as an LXR agonist, a dePPAR α agonist and / or an FXR agonist; an LDL catabolism promoter as described in EP 1022272; a sodium proton exchange inhibitor as described in DE 19622222; an LDL receptor inducer or a steroidal glycoside as described in US Patent No. 5,698,527 and GB 2304106, an antioxidant such as beta carotene, ascorbic acid, α-tocopherol or retinol as described in 94/15592 as well as Vitamin C is an antihomocysteine agent such as folic acid, a folate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid as described in WO 97/35576; and a cholesterol absorption inhibitor, an HMG-CoA synthase inhibitor or an Ianosterol demethylase inhibitor as described in WO 97/48701; a dePPAR δ agonist for the treatment of dyspipidemia; or a protein-1 that binds to a sterol regulatory element (SREBP-1) as described in WO2000 / 050574, for example a sphingolipid, such as ceramide or neutral esfin gomyelenase (N-SMase) or a fragment thereof and lipid synthesis inhibitors or enzymes such as, for example, ACC1 FAS, DGAT1MGAT, GPAT, AMP kinase, CPT1 and SCD1. Preferred deslipidemic agents are Pfizerassim's pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, ezetimibe, fenofibrate and Torcetrapib® as niacin and / or cholestagel.

The compounds of the present patent application may be employed in combination with antihypertensive agents. Examples of antihypertensive agents for use in combination with the compounds of the present application include beta-adrenergic blockers, calcium channel blockers (type L and type T; for example diltiazem, vera-pamil, nifedipine, amlodipine and mibefradil). ), diuretics (e.g. chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, trichrinafen ethacrinic acid, chlortalidone, furosemide tronamide, musolemide, musolide renin, ACE inhibitors (e.g. captopril, zofenopril, fosinopril, enalapril, ceranopril, de-lapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (eg losartan, irbesartan, valsartan, candasartan and talmisartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds described in U.S. Patent Nos. 5,612,359 and 6,043. 265), Dual ET / AII antagonist (eg compounds described in WO 00/01389), neutral endopeptidase inhibitors (NEP), vasopepidase inhibitors (dual NEP-ACE inhibitors) (e.g. omapatrilat and gemopatrilat) and nitrates.

5HT2c modulators could be useful in the treatment of other obesity-associated diseases, including sleep disorders. Therefore, the compounds described in this patent application could be used in combination with therapeutic agents for the treatment of sleep disorders. Examples of therapies suitable for treating sleep disorders for use in combination with the compounds of the present application include melatonin analogs, melatonin doreceptor agonists, ML 1B agonists. barbiturates (e.g. amobarbital, aprobarbital, butabarbital, mephobarbital, pentobarbital, phenobarbital, secobarbital and talbuthal), benzodiazepines (eg diazepam, lorazepam, oxazepam, alpra-zolam, chlordiazepoxide, clonazepam, halazepam, chlorazepam, also specifically including triazolam (Halcion). Other agents for the treatment of sleep disorders include zolpidem (Ambien) and indocron daNeurocrine.

5HT2c modulators may reduce or ameliorate substance abuse or addiction disorders. Therefore, the combination of 5HT2C modulators with agents used to treat addiction disorders may reduce the dose requirement or increase the efficiency of current therapeutic agents for addiction disorders. Examples of agents used to treat abuse or dependence disorders are selective serotonin reuptake inhibitors (SSRIs), methadone, buprenorphine, nicotine and bupropion, and opiate antagonists.

5HT2c modulators may reduce anxiety or depression; therefore, the compounds described in this patent application may be used in combination with antianxiety or antidepressant agents. Examples of antianxiety agents suitable for use in combination with the compounds of this patent application include benzodiazepines (e.g., diazepam, lorazepam , oxazepam, alprazolam, chordia-zepoxide, clonazepam, chlorazepate, halazepam and prazepam), 5HTia doreceptor agonists (eg, buspirone, flesinoxan, gepirone, ipsapirone and serzone), corticotropin-releasing factor (CR1) antagonists and CRFs .

Examples of suitable classes of parause antidepressants in combination with the compounds of the present application include norepinephrine reuptake inhibitors (tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine , paroxetine, citalopram and sertraline), damonoamine oxidase inhibitors (MÀOIs) (isocarboxazide, phenelzine, tranylcupromin, selegiline), reversible monoamine oxidase inhibitors (RIMAs) (moclobe-mida), serotonin (norepinephrine) reuptake inhibitors -lafaxine), corticotropin-releasing factor (CRF) receptor antagonists (Britsol-Myers Squibb US Pat. Nos. 6,642,230; 6,630,476; 6,530,952; 6,579,876; 6,525,656; 6,521,636; 6,518 271, 6,515,005; 6,448,261; 6,399,609; 6,362,180; and 6,358,950), alpha-adrenoreceptor antagonists and atypical antidepressants (bupropion, lithium, nefazodone, trazodone and viloxazine).

The combination of a common conventional 5HT2C modulating antipsychotic drug could further improve the reduction of symptoms in the treatment of human psychosis. Still, such a combination could enable rapid symptom reduction, reducing the need for chronic treatment with antipsychotic agents. Such a combination could further reduce the need for efficient antipsychotic doses, resulting in a reduced probability of developing motor dysfunction typical of chronic antipsychotic treatment.

Examples of antipsychotic agents suitable for use in combination with the compounds of the present patent application include phenothiazine classes (chlorpromazine, mesoridazine, thioridazine, acetophenazine, flufenazine, perphenazine and trifluoperazine), thioxanthine (chlorprothixene, thiotixenzepine), heterocyclic (clozapine, olanzepine and aripiprazole), butyrophenone (haloperidol), diphenylbutylpiperidine (pimozide) and indolone (molindole-na) antipsychotic agents. Other antipsychotic agents of potential therapeutic value in combination with the compounds in the present patent application include loxapine, sulpiride and risperidone.

The combination of the compounds in the present patent application with conventional antipsychotic drugs could further provide an improved therapeutic effect for the treatment of schizophrenic disorders as described above for manic disorders. As used herein, schizophrenic disorders include paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia, schizophreniform disorder, schizoaffective disorder, delusion disorder, rapid psychotic disorder, and unspecified disorder. Examples of suitable antipsychotic drugs for combination with the compounds in the present application include the above-mentioned antipsychotic agents, as well as dopamine receptor antagonists, muscarinic receptor agonists, 5HT2a receptor antagonists and partial 5HT2A receptor antagonists or agonists / dopamine (e.g. olanzepine, aripiprazole, risperidone, ziprasidone).

The compounds described in the present patent application may be used to enhance the effects of cognition enhancing agents such as acetylcholinesterase inhibitors (e.g. tacognagent active in Cognex®), ADHD agents (e.g. methylphenidate, α-tomoxetine the active agent in Strattera® and histamine antagonists 3), muscarinic receptor 1 -gonists (eg milameline), nio-cotinic agonists, glutamic acid receptor modulators (AMPA and NMDA) such as memantine and agents nootropics (eg piracetam, Ievetirace-tam). Examples of therapies suitable for the treatment of Alzheimer's disease and cognitive disorders for use in combination with the compounds of the present application include donepezil, tacrine, revastigraine, 5HT6 receptor antagonists, gamma secretase inhibitors, beta secretase inhibitors, SK channel blockers, Maxi-K blockers and KCNQs blockers.

The compounds described in this patent application may be used to enhance the effects of agents used in the treatment of Parkinson's disease. Examples of agents used to treat Parkinson's Disease include: Ievadopa with or without a COMT inhibitor, antiglutamatergic drugs (amantadine, riluzole), alpha-2 adrenergic antagonists such as idazoxan, opiate antagonists such as naltrexone, others dopamine agonists or carrier modulators such as ropinirole or pramipexole or neurotrophic factors such as glial-derived neurotrophic factor (GDNF).

The compounds described in this patent application may be used in combination with agents used to treat erectile adhesion. Examples of suitable treatment for erectile dysfunction include sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis). Other compounds that could be used in combination for erectile dysfunction include yohimbine, phentolamine and papaverine.

The compounds described in this patent application may be used in combination with suitable anti-inflammatory agents. Examples of suitable anti-inflammatory agents for use in combination with the compounds of this patent application include prednisone, dexamethasone, cyclooxygenase inhibitors (i.e. COX-1e and / or COX-2 inhibitors such as NSAIDs, aspirin, indomethacin, ibuprofen, pyroxy-cam, Naproxen®, Celebrex®, Vioxx®, Arcoxia® and Bextra®), CTLA4- agonists / antagonists lg, CD40 Ligand antagonists, IMPDH inhibitors such as mycophenolate (CelICept®), integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-inhibitor 1, tumor necrosede factor (TNF) antagonists (e.g., infliximab, OR1384, including TNF-alpha inhibitors such as tenidap, anti-TNF antibodies or soluble TNFtal receptor such as etanorcept (Enbrel®), Remicade®, rapamycin ( sir olimus or Rapa-mune) and Ieflunomide (Arava)), prostaglandin synthesis inhibitors, bude-sonide, clofazimine, CNI-1493, CD4 antagonists (eg prilixi-mab), p38 mitogen-activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors, and therapies for treating irritable bowel syndrome (e.g., Zelnorm® and Maxi-K® opening agents such as those described in US Patent No. 6,184,231B1).

Examples of such other therapeutic agents that may be used in combination with 5HT2c modulators include the following: cyclosporins (e.g. cyclosporin A), anti-IL-2 receptor (Anti-Tac), anti-ti-CD45RB, anti-CD2 , anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, OKT3 monoclonal antibody, CD40 and gp39 interaction blocking agents, such as antibodies specific for CD40 and / or gp39 (ie CD154 ), fusion proteins constructed from CD40 and gp39 (CD40lg and CD8gp39), inhibitors such as nuclear translocation inhibitors, NF-kappa B function such as deoxyspergualin (DSG), gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, anticytokines such as anti-IL-4 or fusion proteins of IL-4 and PDE 4 inhibitors such as Ariflo and PTK inhibitors described in the following US patent applications, incorporated by hereby incorporated by reference in their entirety: Ser. No. 09 / 097,338, filed June 15, 1998; No. 2 of Ser. 09 / 094,797, filed June 15, 1998; Ser. No. 09 / 173,413, filed October 15, 1998; and Ser. No. 09 / 262,525, filed March 4, 1999. See further the following documents and references cited herein and incorporated herein by reference: Hollenbaugh, D. and others, "Cleavable CD40lg Fusion Proteins and the Binding to Sgp39", J. Immunol. Methods (Netherlands), 188 (1), pp. 1-7 (December 15, 1995); Hollenbaugh, D. et al., "The Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Is a Ligand for the CD40 Receiver: Expression of a Soluble Form of Gp39 with B Cell Co-Stimulatory Activity, "EMBO J (England), 11 (12), pp. 4,313-4321 (December 1992); and Moreland, L. W. et al., "Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Neurosis Receptor Factor (P75) -Fc Fusion Protein", New England J. of Medicine, 337 (3), pp. 631-740. 141-147 (1997).

The other prior therapeutic agents, when employed in combination with the compounds of the present patent application, may be used, for example, in the amounts indicated in the Physicians' DeskReference (PDR) or as otherwise determined by one of ordinary skill in the art.

The compounds of formula I of the patent application may be administered orally or parenterally, such as subcutaneously or intravenously, as well as through nasal, transdermal, rectal or sublingual application to various mammalian species known to be subject to such diseases, for example, humans, in an amount effectively within the dosage range of from about 0.2 to 1000 mg, preferably from about 1 to 100 mg in a one, two or four divided daily doses.

The compounds of formula I may be administered for any of the uses described herein by any suitable means, for example, orally, such as in tablet, capsule, granule or powder form; sublingually; oral; parenteral, such as by subcutaneous, intravenous, intramuscular or intracisternal injection or infusion techniques (for example, in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasal, including administration to the nasal membranes, such as through an inhalation spray; topical, such as in the form of a cream or ointment; or rectally as in the form of suppositories, in unit dosage formulations containing non-toxic pharmaceutically acceptable carriers or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of appropriate pharmaceutical compositions comprising the present compounds or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally.

Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose to impart mass, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and flavoring sweeteners or agents such as those known in the art. ; and immediate deliberation tablet which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other former excipients, binders, diluents, disintegrating agents, diluents and lubricants such as known in the art. The compounds of formula I may also be supplied through the oral cavity by sublingual and / or buccal administration. Freeze-dried molded, compressed or compressed tablets are examples of forms that may be used. Exemplary compositions include those formulating the present compound (s) with rapidly dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. High molecular weight excipient formulations such as celluloses (α-vicel) or polyethylene glycols (PEG) may also be included. Such formulations may further include an excipient to aid adhesion to mucous membranes such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), carboxy methyl cellulose desodium (SCMC), maleic anhydride copolymer (e.g. Gantrez ) agents for controlling release such as polyacrylic copolymer (eg Carbopol 934). Lubricants, gliding agents, flavorings, coloring agents and stabilizers may also be added for ease of manufacture and use.

Examples of compositions for administration by aerosolnasal or inhalation include saline solutions which may contain, for example, benzyl alcohol or other preservatives, absorption enhancers to increase biological availability and / or other solubilizing or dispersing agents. such as are known in the art.

Examples of parenteral compositions include injectable solutions or suspensions which may contain, for example, suitable non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, a chloride solution isotonic sodium or other suitable dispersing or wetting agents, including mono- or diglycerides and fatty acids, including oleic acid or Cremaphor.

Examples of rectal administration compositions include suppositories which may contain, for example, an appropriate non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but are liquefied and non-irritating. / or dissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topical carrier such as Plastibase (polyethylene gelled mineral oil).

It will be appreciated that the specific dose level and tapping frequency for any particular individual may be varied and will depend upon a variety of factors including the activity of the particular compound employed, the metabolic stability and the period of action of such compound. the type, age, body weight, general health, sex and diet of the individual, the mode and time of administration, the rate of excretion, the combination of drugs and the severity of the particular health condition. .

PHARMACOLOGICAL ANALYSIS

Pharmacological analysis of each compound for antagonist or agonism of 5-HT 2a, 5-HT 2b and 5-HT 2c receptors consisted of in vitro and in vivo studies. In vitro analyzes included determinations of Kj at 5-HT2a, 5-HT2B and 5-HT2c receptors and an assessment of functional activity (ie agonism or antagonism) in each receptor class through IP3 hydrolysis assays. . Additional receptor assays were performed to assess receptor specificity of 5-HT2C receptors with respect to monoamine and nuisance receptors (e.g. histamine, dopamine and muscarinic). A compound is considered active as an S-HT2 umagonist if it has an EC50 value or a Kj value less than approximately 50 micromolar; preferably less than about 1.0 micromolar; more preferably less than approximately 0.1 micromolar. Using the assays described herein, it has been shown that the compounds of the present patent application have a smaller EC 50 value that is approximately 50 micromolar to the 5-HT 2 agonism.

In vivo assays evaluated compound activity in a variety of behavioral paradigms including acute and chronic feeding models, anxiety and depression models (trapped helplessness, high positive maze, Geller-Siefter, taste-conditioned aversion, taste reactivity , satiety sequence). In aggregate, these models reflect activity as a 5-HT2c agonist (feeding models, anxiety models, depression models) and provide some indication as to biological availability, metabolism and pharmacokinetics.

Radioactive ligand binding experiments were performed on recombinant human 5-HT2a, 5-HT2B and S-HT2c receptors expressed on HEK293E cells. The affinities of the compounds of the present application for binding to these receptors are determined by their ability to compete for binding with -1- (2,5-dimethoxy-4-iodophenyl) -2-amino-propane (DOI) or [3 H] -lysergic acid (LSD) diethylamide at 5-HT2A, 5-HT2B or 5-HT2C receptors. General references for binding assays include 1) Lucaites VL, Nelson DL, Wainscott DB, Ba-ez M (1996) Subtype receptor and density determine the coupling repertoire of the 5-HT2 receptor subfamily. Life Sci., 59 (13): 1081-95. Glennon RA, Seggel MR, Soine WH, Herrick-Davis K, Lyon RA, Titeler M (1988) -1- (2,5-dimethoxy-4-iodophenyl) -2-amino-propane: an iodinated radioligand thatspecifically Iabels the agonist high-affinity state of 5-HT2 serotonin receptors.J Med. Chem. (1988) 31 (1): 5-7 and 3 Leonhardt S, Gorospe E, Hoffman BJ, Teitler M (1992) Molecular pharmacological differences in the interaction of serotonin with 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors. MolPharmacoI., 42 (2): 328-35.

The functional properties of the compounds (efficiency and potency) were determined in whole cells expressing 5-HT2Ai 5-HT2B or 5-HT2c receptors by assessing their ability to stimulate or inhibit phosphoinositol hydrolysis and / or receptor-mediated intracellular calcium release. The procedures used are described below.

IN VITRO CONNECTION TESTS

Stable Expression of 5-HT2A, 5-HT2b and 5-HT2c Receptors in HEK293E Cells

Stable cell lines were generated by transfecting 293EBNA cells with plasmids containing the human 5-ΗΤ2α, 5-ΗΤ2β or 5-HT2C receptor cDNA (isoforms edited relative to INI, INV, VNV or VGV RNA) using phosphate. calcium. These plasmids also contained the immediate initial cytomegalovirus (CMV) promoter to control EBV receptor and oriP expression for maintenance in the form of an extrachromosomal element and the E. colip hph gene to produce resistance to hygromycin B (Horlick and others, 1997). The transfected cells were maintained in Dulbecco's Modified Eagle (DMEM) medium containing 10% fetal bovine serum dialysed at 37 ° C in a humid environment (5% CO2) for 10 days. 5-HT2A cells were adapted to a shaker culture for mass processing while other strains had to be maintained as adherent cultures. On the day of collection, the cells were washed in phosphate buffered saline (PBS), counted and stored at -80 ° C.

Membrane Preparation

On the day of the assay, whole cell pellets (containing approximately 1 X 10 8 cells) expressing the S-HT2a, 5-HT2b or 5-HT2c receptor were thawed on ice and homogenized in 50 mM TrisHCI (pH 7.7 ) containing 1.0 mM EDTA using a Brinkman Politron (PT-10, setting 6 for 10 s). The homogenate was centrifuged at 48,000 χ g for 10 min and the resulting pellet was washed twice through repeated homogenization and centrifugation steps. The final pellet was resuspended in tissue buffer and protein determinations were made using the Biconiconic Acid (BCA) assay (Pierce Co., IL) using bovine albumin as the standard.

Radioactive Ligand Binding Assays for 5-HT2Aj 5-ΗΤ2β β 5-HT2c Receptors

Radioactive ligand binding studies were performed to determine the binding affinities (Ki values) of the compounds relative to human 5-HT2A, 5-HT2b and 5-HT2c receptors (Fitzgerald et al., 1999). Assays were conducted in disposable 96-well polypropylene plates (Costar Corp., Cambridge, MA) and were initiated by adding 5-HT2a, 5-HT2b or 5-HT2c membrane homogenate in the tissue buffer (10-30 ( g / well) in the assay buffer (50mM Tris HCl1 0.5mM EDTA, 10mM Pargillin, 10mM MgSO4,

0.05% ascorbic acid, pH 7.5) containing DOI for 5-HT2Ae 5-HT2C (0.3-0.5 nM final) or [3H] LSD (1-2.0 nM final) receptors ) for the 5-HT 2b receptor, with or without the competing drug (i.e. the newly synthesized chemical entity).

For a typical competition experiment, a fixed concentration of radioactive ligand competed with concentrations in duplicate ligand (12 concentrations ranging from 10 picomolar to 10 micromolar). Reaction mixtures were incubated to equilibrium for 45 min 37 ° C and terminated by rapid filtration (Packard cell harvester; Per-kin-Elmer) over GFB fiberglass filters that had been pre-soaked at 0 ° C. 3% polyethyleneimine. The filters were washed in 50mM ice cold Tris HCl buffer (pH 7.5) and then counted in a Top Count (Packard).

Phosphhohositide Hydrolysis Studies

The ability of newly synthesized compounds to stimulate phosphoinositide (PI) hydrolysis was monitored in whole cells using a variation (Egan et al., 1998) from a previously described protocol (Berridge et al., 1982). HEK293E cells expressing the human 5-HT2A1 5-HT2B or 5-HT2c receptor were suspended with 0.5 mM EDTA and plated at a density of 100,000 / well in poly-D-lysine coated 24-well plates ( Becton Dickinson, Bedford, MA) in Dulbecco's Modified Eagle Serum (DMEM; Gibco BRL) containing high glucose content, 2 mM glutamine, 10% dialysis fetal calf serum, 250 pg / mL hygromycin B and 250 pg / ml G418. After a period of 24-48 h, growth medium was removed and replaced with DMEM without fetal calf serum and inositol (Gibco BRL). The cells were then incubated with DMEM (without serum and inositol) containing a final concentration of 0.5 uCi / well of myo [3 H] inositol for 16-18 h. After incubation, cells were washed with DMEM (without serum or inositol) containing 10 mM LiCl and 10 μΜ pargillin and then incubated for 30 min with the same medium, but now containing one of several test compounds. by aspirating the medium and freezing-thawing the cells. Phosphoinositides [3 H] were extracted with chloroform / methanol (1: 2 v / v), separated by anionic chromatography (Bio-Rad AGI-X8 resin) and counted by liquid scintillation spectroscopy as described above (Egan and others, 1998).

Calcium Fluorescence Studies

The ability of newly synthesized compounds to stimulate calcium affluence was monitored in whole cells using a protocol described previously (Fitzgerlad et al, 1999). HEK293E cells expressing the human 5-HT2c or 5-HT2b receptor were suspended with 0.5 mM EDTA and plated at a density of 50,000 / well in poly-D-lysine-coated 96-well plates (Biocoat; Becton Dickinson, Bedford, MA) in Dulbecco's Modified Eagle Serum (DMEM; Gibco BRL) containing high glucose, 2 mM glutamine, 10% dialysis fetal calf serum, 250 pg / mL hygromycin B is 250 pg / ml G418. After a period of 24 h, plates are removed from the incubator and an equivalent volume of Charge Buffer (Hanks BSS with 200 mM HEPES, pH 5.98) containing calcium discoloration reagent (Fluo-3) is added in each (100 μΙ_ per well for 96-well plates and then incubated for 1 hour at 37 ° C. After cell dye loading the plates are transferred to the FLIPR. Test compounds are added to the plate as a Concentration response and changes in fluorescence units caused by calcium influx are monitored over a period of three seconds.

Data Analysis

Apparent equilibrium dissociation constants (Kis) from competition experiments were calculated using an interactive nonlinear regression curve fitting program (Excelfit eTA Activity Base). For P1 hydrolysis and FLIPR experiments, EC50s were calculated using a one-site 'pseudo' Hill model: y = ((Rmax-Rmin) / (1 + R / EC50) nH)) + Rmax where R = response (Graph-Pad Prism; San Diego, CA). Emax (maximal response) was derived from the adjusted maximum curve (net IP stimulus) for each compound. Intrinsic activity (IA) was determined by expressing a compound's Emax as a percentage of 5-HT Emax (AI = 1.0).

Efficacy Models for Assessing Food Consumption and Weight Loss

Acute overnight feeding trial. Compost are evaluated for their ability to reduce food consumption during the dark cycle, which is the most active period of rat feeding. 344 Fischer rats are trained in a fixed ratio three-response (FR3) paradigm that requires them to press a bar 3 times consecutively to obtain a food pellet. The number of bar pressures that occur throughout the darkness cycle It can be monitored electronically as a measure of food intake by the animal. Rats receive oral or intraperitoneal doses of the test compound 30 minutes before the start of the dark cycle. The treated animals are then placed in individual operating boxes for 15 hours (12h dark cycle and the first hours of light cycle). Food intake in compound-treated animals is compared with vehicle-treated animals to determine percent reductions in food intake. Simultaneous measurements of water intake and Iocomotor activity are also made during the assessment period for potential adverse effects.

Chronic Feeding Assay

The compounds are evaluated for their long-term impact on food intake and body weight in a chronic treatment para-digom of three to fourteen weeks in Spra-gue-Dawley rats (initial weight of -450 g). Sprague-Dawley male rats were pre-manipulated for one week prior to the start of dosing during which time they are also evaluated for food-eating behavior. Rats are then assigned to treatment groups. Rats receive doses with the vehicle or compound by forced oral ingestion. Food intake and body weights are cumulatively assessed at the end of each treatment week and compared with those of the animals treated with the vehicle. In some studies food ingestion is measured daily to assess the impact of reduced food consumption on animals fed as a pair. At the end of the study period the animals are evaluated for changes in body composition using DEXA and then sacrificed for the purpose of verifying changes in various blood plasma parameters.

DOSAGE AND FORMULATIONS

The serotonin agonist and serotonin antagonist compounds of this patent application may be administered as a treatment for the control or prevention of central nervous system disorders including obesity, anxiety, depression, psychosis, schizophrenia, sleep disorders and sexual disorders, migraine and other health conditions associated with headache pain, social phobias and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility through any means that produce contact of the active agent with the active agent site of action, ie receptors 5-HT 2 in the body of a mammal. They may be administered by any means available for use in combination with pharmaceutical agents, as a single therapeutic agent or in a combination of therapeutic agents. They may be administered alone, but preferably are administered with a selected pharmaceutical carrier based on the route of administration of choice and standard pharmaceutical practice.

The compounds of the present application may be administered in oral dosage forms such as tablets, capsules (each of which includes time-limited or controlled release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. . Similarly, they may also be administered intravenously (bolus or infusion), intraperitoneal, subcutaneous or intramuscular. Also, they may also be administered by in-house delivery, transdermal delivery and suppository or depot delivery all dosage forms well known to those of ordinary skill in the pharmaceutical arts.

The dosage administered, of course, will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and oppression of the recipient; the nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; and the desired effect. With the general guidance purpose, a daily dose of active ingredient can be expected to be from about 0.001 to about 1000 milligrams per kilogram body weight, with the preferred dose being from about 0.01 to about 100 mg / kg; with the most preferred dose being from about 0.01 to about 30 mg / kg. Advantageously, the compounds of the present application may be administered in a single daily dose or the total daily dose may be administered in divided doses of two, three or three. or four times daily.

Dosage forms of the compositions suitable for administration contain from about 0.5 mg to about 100 mg of the active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of approximately 0.5-95% by weight based on the total weight of the composition. The active ingredient may be administered orally in solid dosage forms such as capsules, tablets and powders or in liquid dosage forms such as elixirs, syrups and suspensions. It may also be administered parenterally in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and empiric carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents may be used for compressed tablet production. Both tablets and capsules may be produced in the form of sustained release products to provide continuous release of medication over a period of hours. Pressed tablets may be sugar coated or film-coated to mask any unpleasant taste and protect the atmosphere from the atmosphere or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring and flavoring agents to increase patient acceptance.

In general, water, a suitable oil, saline, dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering substances. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field.

Pharmaceutical dosage forms useful for the administration of the compounds of this patent application may be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling two standardized hard gelatin capsules each with 100 mg of the active ingredient powder, 150 mg of lactose1 50 mg of cellulose and 6 mg of stearic magnesium.

Soft Gelatin Capsules

A mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected via a positive displacement pump into the gelatin to form capsules. soft gelatin containing 100 mg of the active ingredient. The capsules should then be washed and dried.

Tablet

A large number of tablets may be prepared by conventional procedures such that the dosage unit is 100 mg active ingredient, 0.2 mg colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Suspension

An aqueous suspension may be prepared for oral administration so that each 5 ml contains 25 mg of the finely divided active ingredient, 200 mg sodium carboxymethyl cellulose, 5 mg benzoate sodium, 1.0 g sorbitol solution, U.S.P. and 0.025 mg vanillin.

Injectable

A parenteral composition suitable for injection administration may be prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is sterilized by commonly used techniques.

EXAMPLES

EXAMPLE 1

6,9-Dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 49 </formula>

To a solution of 1- (2,5-dimethylphenyl) hydrazine hydrochloride (4.26 g, 24.7 mmol) and 4-piperidone hydrochloride monohydrate (3.79 g, 24.7 mmol) in EtOH (43 mL ) 12 N HCl (4.12 mL, 49.4 mmol) was added at 20 ° C. The reaction mixture was stirred at 80 ° C for 3 h, filtered to afford a white solid (4.35 g, 18.5 mmol). The solid was recrystallized twice from MeOH at 75 ° C to obtain the title compound (2.06 g, 8.78 mmol): MS (ES) 201.2 (M + H).

EXAMPLE 2 6,8-Dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 50 </formula>

To a solution of 1- (2,4-dimethylphenyl) hydrazine hydrochloride (500 mg, 2.89 mmol) and 4-piperidone hydrochloride monohydrate (444 mg, 2.89 mmol) in EtOH (5.0 mL) was added HCl at 12 N (0.48 mL, 49.4 mmol) at 20 ° C. The reaction mixture was stirred at 80 ° C for 3 h, filtered and washed with ice cold EtOH to afford the title compound as a white solid (640 mg, 2.71 mmol): MS (ES) 201.2 (M + H).

EXAMPLE 3

6,7-Dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 50 </formula>

The title compound was prepared as a white solid (11.0 g, 46 mmol) following the procedures of example 1 starting from 1- (2,3-dimethylphenyl) hydrazine hydrochloride (10.0 g, 58 mmol), 4-piperidone hydrochloride monohydrate (8.9 g, 58 mmol), 12 N HCl (10 mL, 120 mmol) and EtOH (100 mL): MS (ES) 201.2 (M + H).

EXAMPLE 4

7,9-Dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 50 </formula>

To a solution of 1- (3,5-dimethylphenyl) hydrazine hydrochloride (1.2g, 7.2 mmol) and 4-piperidone hydrochloride monohydrate (1.1 g, 7.2 mmol) in EtOH (21 1 mL) was added 12 N HCl (1.8 mL, 21.5 mmol) at 20 ° C. The reaction mixture was stirred at 75 ° C for 4.5 h, filtered and washed with ice cold EtOH to obtain the title compound as a white solid (1.5 g, 6.2 mmol: MS (ES) 201, 2 (M + H).

EXAMPLE 56,9-Dichloro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 51 </formula>

1- (2,5-Dichlorophenyl) hydrazine (89 mg, 0.5 mmol) and 4-piperidone hydrochloride monohydrate (77 mg, 0.5 mmol) in CF 3 CH 2 OH (1.5 mL) were heated to 75 ° C for 15 min to form a translucent solution. To the reaction mixture was added 12 N HCl (0.083 mL, 1.0 mmol). The reaction mixture was heated at 75 ° C for 24 h, cooled to 20 ° C, filtered and washed with CF 3 CH 2 OH. The solid was dissolved in H 2 O, basified with 1 N NaOH to pH 12-13 and extracted with CHCl 3. The combined organic layer was dried over MgSO 4, filtered and concentrated in vacuo to afford the title compound as a light brown solid. (74 mg, 0.32mmol): MS (ES) 241.0 (M + H).

EXAMPLE 6

6,7-Dichloro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole

<formula> formula see original document page 51 </formula>

1- (2,3-Dichlorophenyl) hydrazine (4.7 g, 26.6 mmol) and 4-piperidone hydrochloride monohydrate (4.1 g, 26.6 mmol) in CF 3 CH 2 OH (54 mL) were refluxed. for 3 h to form a translucent solution followed by the formation of a light yellow precipitation. To the reaction mixture was added 12 N HCl (4.4 mL, 52.8 mmol). The reaction mixture was refluxed for 4 days, cooled to 20 ° C, filtered and washed with CF 3 CH 2 OH. The solid was dissolved in H 2 O, basified with 1 N NaOH to pH 12-13 and extracted with CHCl 3. The combined organic layer was dried over MgSO 4, filtered and concentrated in vacuo to afford the title compound as a light brown solid. (6.1 g, 25.3 mmol): MS (ES) 241.0 (M + H).

EXAMPLE 7

6,8-Difluoro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole <formula> formula see original document page 52 </formula>

To a solution of 1- (2,4-difluorophenyl) hydrazine hydrochloride (91mg, 0.5 mmol) and 4-piperidone hydrochloride monohydrate (77 mg, 0.5 mmol) in EtOH (1.5 mL) was added. 12 N HCl (0.083 mL, 1.0 mmol) at 20 ° C. The reaction mixture was stirred at 15 ° C for 15 h, cooled to 20 ° C and concentrated in vacuo. The residue was purified by prep. HPLC. reverse phase (H 2 O / CH 3 CN) followed by basic work up to provide the title compound as a yellow solid (38 mg, 0.18 mmol): MS (ES) 209.1 (M + H).

EXAMPLE 8

7,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole

<formula> formula see original document page 52 </formula>

To a solution of 1- (3,4-dimethylphenyl) hydrazine hydrochloride (3.7g, 21.5 mmol) and 4-piperidone hydrochloride monohydrate (3.3 g, 21.5 mmol) in EtOH (63.2 mL) ) 12 N HCl (5.4 mL, 64.5 mmol) was added at 75 ° C. The reaction mixture was stirred at 75 ° C for 3 h, filtered and washed with ice cold EtOH to a 3: 1 mixture of the title compound and its isomer-isomer (4.8 g, 17.6 mmol). The mixture (15 mg) was purified by H-PLC (10-20% CH 3 CNZH 2 O) to obtain the title compound (3.3 mg, 0.012 mmol): MS (ES) 201.22 (M + H).

EXAMPLE 9

8,9-Dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 52 </formula>

The title compound was obtained as a small product from the synthesis of Example 8: MS (ES) 201.22 (M + H).

Example 107,9-Dichloro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 53 </formula>

The title compound was prepared as a yellow solid (55 mg, 46 mmol) following the procedures of example 5 by taking 1- (3,5-dichlorophenyl) hydrazine hydrochloride (89 mg, 0.5 mmol), 4-piperidone hydrochloride monohydrate (77 mg, 0.5 mmol), 12 N HCl (0.083 mL, 1.0 mmol) and CF 3 CH 2 OH (1.5 mL): MS (ES) 241.0 (M + H).

EXAMPLE 11

9-Fluoro-6-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 53 </formula>

To a solution of 1- (5-fluoro-2-methylphenyl) hydrazine hydrochloride (2.2 g, 12.5 mmol) and 4-piperidone hydrochloride monohydrate (1.9 g, 12.5 mmol) in EtOH (21 NaCl, 5 mL) was added 12 N HCl (3.1 mL, 37.5 mmol) at 75 ° C. The reaction mixture was stirred at 75 ° C for 5 h, filtered and washed with ice cold EtOH to obtain the title compound. (0.64 mg, 2.7 mmol): MS (ES) 205.3 (M + H).

EXAMPLE 12

9-Chloro-6-methyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 53 </formula>

To a solution of 1- (5-chloro-2-methylphenyl) hydrazine hydrochloride (1.0 g, 5.2 mmol) and 4-piperidone hydrochloride monohydrate (0.79 g, 5.2 mmol) in EtOH (8 12 mL) was added 12 N HCl (1.3 mL, 15.5 mmol) at 75 ° C. The reaction mixture was stirred at 75 ° C for 15 h, filtered and washed with ice cold EtOH to obtain the title compound (0.65 mg, 2.5 mmol): MS (ES) 221.1 (M + H). EXAMPLE 13

8-Methoxy-6-methyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 54 </formula>

To a solution of 1- (4-methoxy-2-methylphenyl) hydrazine (0.16 g, 1.0 mmol) and 4-piperidone hydrochloride monohydrate (0.16 g, 1.0 mmol) in EtOH (3.0 mL) ) 12 N HCl (0.26 mL, 3.0 mmol) was added at 20 ° C. The reaction mixture was stirred at 75 ° C for 20 h. EtOH was removed by vacuum, the residue was basified by 1 N NaOH to pH> 12, extracted with CHCl3. The residue was purified by HPLC (0-100% CH 3 CN / H 2 O) to obtain the title compound along with an impurity (54 mg). The mixture was solubilized in H 2 O and extracted with CHCl 3. The aqueous phase was basified by 1 N NaOH to pH> 12, extracted with CHCl3. The combined organic solution was washed with brine and dried over MgSO 4, filtered and concentrated in vacuo to afford the title compound as a golden solid (16.2 mg, 0.07 mmol): MS (ES) 217, 2 (M + H).

EXAMPLE 14

7-Chloro-6-methyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 54 </formula>

Step A. A solution of sodium nitrite (1.2 g, 17.0 mmol) and H 2 O (3.5 mL) was added dropwise at 0 ° C to a solution of 3-chloro-2-methylbenzenamine (2.0 g, 14.1 mmol) in 12 N HCl (33.5 mL) and TFA (4.3 mL). The reaction mixture was stirred at 0 ° C for 1 h followed by the dropwise addition of a solution of tin (II) chloride (5.9 g, 31.0 mmol) in 12 N HCl (8.4 mL) and H 2 O (1 0.1 mL) at 0 ° C. The reaction mixture was stirred for 15 h at 20 ° C and was filtered to afford 1- (3-chloro-2-methylphenyl) hydrazine hydrochloride as a brown solid (2.5 g, 13.0 mmol).

Step B. A solution of 1- (3-chloro-2-methylphenyl) hydrazine (0.25 g, 1.6 mmol), 4-piperidone hydrochloride monohydrate (0.24 g, 1.6 mmol) and a12 N HCl HCl (0.4 mL, 4.7 mmol) in EtOH (4.7 mL) was stirred at 75 ° C for 2 h.

The reaction mixture was filtered to obtain the title compound (0.13.0.51 mmol) as a white solid: MS (ES) 219.2 (M-H).

EXAMPLE 15

7-Chloro-6-fluoro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 55 </formula>

Step A. A solution of sodium nitrite (12.5 g, 85.9 mmol) and H 2 O (21.4 mL) was added dropwise at 0 ° C to a solution of 3-chloro-2-fluorobenzenamine hydrochloride (2 2.0 g, 8.45 mmol) in 12 N HCl (203.3 mL) and TFA (23.4 mL). The reaction mixture was stirred at 0 ° C for 1 h followed by the dropwise addition of a solution of tin (II) chloride (35.8 g, 188.9 mmol) in 12 N HCl (51.6 mL) and H 2 O (6 , 8 mL) at 0 ° C. The reaction mixture was stirred for 15 h at 20 ° C and was filtered and placed under vacuum to provide 1- (3-chloro-2-fluorophenyl) hydrazine hydrochloride as a golden solid (23.5 g, 119.0 mmol).

Step B. A solution of 1- (3-chloro-2-fluorophenyl) hydrazine hydrochloride (3.35 g, 17.0 mmol) and 4-piperidone hydrochloride monohydrate (2.6 g, 17.0 mmol) in IPA (50.0 mL) was stirred at 20 ° C for 10 min, followed by stirring at 80 ° C for 15 h. The reaction mixture was filtered to obtain the title compound (3.2g, 12.5 mmol) as a tan solid: MS (ES) 269.0 (M-H).

Example 16

6-Bromo-9-fluoro-6-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole

<formula> formula see original document page 55 </formula>

Step A. 1- (2-Bromo-5-fluorophenyl) hydrazine hydrochloride was prepared as a white solid (5.8 g, 24 mmol) following the procedures of example 14 Step A starting from 2-bromo-5-fluoroaniline (4.9 g, 25.8 mmol), sodium nitrite (2.2 g, 31 mmol), SnCl 2 (10.8 g, 56.8 mmol), 12 N HCl (62 mL + 16 mL), TFA (8.0 mL) and H2O (6.5 mL + 2.0 mL). Step B. A 1- (2-bromo-5-fluorophenyl) hydrazine hydrochloride solution (1.0 g, 4.1 mmol) ), 4-piperidone hydrochloride monohydrate (636 mg, 4.1 mmol) and 12 N HCl (0.68 mL, 8.2 mmol) in EtOH (10 mL) was stirred at 75 ° C for 15 h. The reaction mixture was cooled to 20 ° C and filtered. The solid was dissolved in H 2 O, basified with 1 N NaOH to pH> 12 and extracted with CHCl 3. The combined organic solution was dried over MgSO 4, filtered and vacuum concentrated to obtain the title compound as a yellow solid (54 mg, 0.20 mmol): MS (ES) 219.2 (M-H).

Example 17

6-Bromo-9-chloro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 56 </formula>

Step A. A 50 ° C solution of tin (II) chloride (12.0 g, 63.4 mmol) in EtOH (19 mL) was added in 1-bromo-4-chloro-2-nitrobenzene ( 3.0 g, 12.7 mmol) followed by the addition of 12 N HCl (19.0 mL, 0.02 mmol). Reaction mixture was stirred at 60 ° C for 70 min. EtOH was removed under vacuum, the residue was basified by NaOH to pH> 12 and extracted with CHCl3. The combined organic solution was washed with brine and dried over MgSO 4, filtered and concentrated in vacuo to afford 2-bromo-5-chlorobenzenamine (2.33 g, 11.3 mmol).

Step B. A solution of sodium nitrite (0.63 g, 9.2 mmol) and H 2 O (1.9 mL) was added dropwise at 0 ° C to a solution of 2-bromo-5-chlorobenzenamine (1.6 mL). g, 7.7 mmol) in 12 N HCl (18.2 mL) and TFA (2.31 mL). The reaction mixture was stirred at 0 ° C for 1 h followed by the dropwise addition of a solution of tin (II) chloride (3.1 g, 16.9 mmol) in 12 N HCl (4.6 mL) and H 2 O (0 , 6 mL) at 0 ° C. The reaction mixture was stirred for 15 h at 20 ° C and was filtered and placed under vacuum to afford 1- (2-bromo-5-chlorophenyl) hydrazine hydrochloride (2.0 g, 7.8 mmol).

Step C. A solution of 1- (2-bromo-5-chlorophenyl) hydrazine hydrochloride (0.10 g, 0.39 mmol) and 4-piperidone hydrochloride monohydrate (59.6 mg, 0.39 mmol) in EtOH (1.14 mL) was stirred at 75 ° C for 30 min. The reaction mixture was cooled and filtered to obtain 1- (2-bromo-5-chlorophenyl) -2- (piperidin-4-ylidene) hydrazine hydrochloride (73.3 mg, 0.22 mmol).

Step D. 12 N HCl (0.05 mL, 0.65 mmol) was added to a 1- (2-bromo-5-chlorophenyl) -2- (piperidin-4-ylidene) hydrazine hydrochloride solution (72, 8mg, 0.22mmol) in EtOH (0.63mL) and was reacted in a microwave reactor at 180 ° C for 2 min. The reaction mixture was cooled and filtered to obtain the title compound (13.1 mg, 0.04 mmol) as a white solid: MS (ES) 286.89 (M + H).

Step A. To a solution of 4-methyl-2-nitrobenzenamine (1.2 g, 7.9 mmol) in acetonitrile (5 mL) was added a solution of tert-butyl nitrite (1.2 g, 11.8 mmol). ) and cupric chloride (II) (1.3 g, 9.5 mmol) in acetonitrile (11 mL) dropped via a syringe pump at 20 ° C over a period of 1 h. The reaction mixture was stirred at 65 ° C for 15 h, brought to 20 ° C, poured into 6 N HCl (60 mL) and extracted with diethyl ether. The combined organic solution was dried over MgSO 4, filtered and concentrated in vacuo to afford 1-chloro-4-methyl-2-nitrobenzene (1.35 g, 7.9 mmol).

Step B. A 50 ° C solution of tin (II) chloride (7.5 g, 39.5 mmol) in EtOH (12 mL) was added to 1-chloro-4-methyl-2-nitrobenzene ( 1.4 g, 7.9 mmol) followed by the addition of 12 N HCl (11.9 mL, 142.2 mmol). Reaction mixture was stirred at 60 ° C for 70 min. EtOH was removed under vacuum, the residue was basified by 1 N NaOH to pH> 12 and extracted with CHCl3. The combined organic solution was washed with brine and dried MgSO 4, filtered and concentrated in vacuo to afford 2-chloro-5-methylbenzenamine (0.95 g, 6.7 mmol).

Step C. A solution of sodium nitrite (0.67 g, 9.94 mmol) and H 2 O (2.06 mL) was added dropwise at 0 ° C to a solution of 2-chloro-5-

EXAMPLE 18

6-Chloro-9-methyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 57 </formula> methylbenzenamine (1.2 g, 8.29 mmol) in 12 N HCl (12.8 mL) and TFA (2.5 mL). The reaction mixture was stirred at 0 ° C for 1 h followed by the dropwise addition of a solution of tin (II) chloride (3.5 g, 18.2 mmol) in 12 N HCl (4.9 mL) and H 2 O (0 , 7 mL) at 0 ° C. The reaction mixture was stirred at 15 h at 20 ° C and was filtered to afford 1- (2-chloro-5-methylphenyl) hydrazine hydrochloride as a white solid (0.84 g, 4.3 mmol). Step D. A solution of 1- (2-chloro-5-methylphenyl) hydrazine hydrochloride (0.1g, 0.52 mmol) and 4-piperjdone hydrochloride monohydrate (79.6 mg, 0.52mmol) in EtOH ( 1.5 mL) was stirred at 75 ° C for 15 h. After addition of 12 N HCl (0.13 mL, 1.6 mmol), the reaction was filtered and washed with free EtOH to afford the title compound (65.2 mg, 0.24 mmol): MS ( ES) 221.1 (M + H).

Example 19

8-Bromo-6-iodo-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 58 </formula>

Step A. To a mixture of 4-bromoaniline (27.3 g, 159 mmol) and NaHCO 3 (12.6 g, 150 mmol) in H 2 O was added portionwise powdered powder over 10 min under vigorous stirring at 20 ° C. . The reaction mixture was stirred for a further 2h and then filtered. The filtrate was extracted with Et 2 O 1 and the combined organic layer was dried over MgSO 4, filtered and concentrated in vacuo. The residue was chromatographed (Hex: EtOAc 7: 1) to afford 4-bromo-2-iodoaniline (9.4 g, 31.5 mmol).

Step Β. 1- (4-Bromo-2-iodo-phenyl) hydrazine (5.7 g, 18.3 mmol) was prepared as an orange solid following the procedures of example 14 Step A starting from 4-bromo -2-iodoaniline (6.0 g, 20.1 mmol), sodium nitrite (1.5 g, 22 mmol), SnCl 2 (7.7 g, 40.3 mmol), 12 N HCl (40 mL + 15 mL) and H 2 O (5.0 mL) followed by basic processing.

Step C. To a suspension of 1- (4-bromo-2-iodo-phenyl) hydrazine (4.0 g, 12.8 mmol) and 4-piperidone hydrochloride monohydrate (1.96 g, 12.8 mmol) in IPA (30 mL) was bubbled HCI (gas) for 10 min. The reaction mixture was sealed and then heated at 80 ° C for 2 days. The reaction mixture was cooled to 20 ° C, filtered and washed with ice cold IPA to afford the title compound (2.41 g, 5.8 mmol): MS (ES) 376.9 (M + H).

EXAMPLE 20

6-Chloro-9- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 59 </formula>

To a suspension of 1- (2-chloro-5- (trifluoromethyl) phenyl) hydrazine (1.0 g, 4.7 mmol) and 4-piperidone hydrochloride monohydrate (730 mg, 4.7 mmol) in IPA (13 mL) ) HCl (gas) was bubbled for 10 min. The reaction mixture was sealed and then heated at 75 ° C for 15 h. The reaction mixture was cooled to 20 ° C, filtered and washed with ice cold IPA to afford the title compound (250 mg, 0.80 mmol): MS (ES) 275.1 (M + H).

Step A. 1- (4-Fluoro-2- (trifluoromethyl) phenyl) hydrazine hydrochloride was prepared as a white solid (230 mg, 1.0 mmol) following the procedures of example 14 Step A starting from 4-fluoro-2- (trifluoromethyl) aniline (180 g, 1.0 mmol), sodium nitrite (83 mg, 1.2 mmol), SnCl 2 (418 mg, 2.2 mmol), 12 N HCl ( 2.5 mL + 0.8 mL), TFA (0.4 mL) and H2O (0.5 mL).

Step B. In a microwave-compatible tube, a 1- (4-fluoro-2- (trifluoromethyl) phenyl) hydrazine hydrochloride solution (100 mg, 0.43 mmol) and 4-piperidone (67 mg, 0.44 mmol) ) in IPA (1.5 mL) was saturated with HCl gas and then sealed. The reaction mixture was irradiated in a microwave at 140 ° C for 10 min. The reaction was cooled to 0 ° C and filtered. The solid was washed with ether to provide the HCl salt of the title compound (75 mg, 0.24mmol) as an off-white solid. A solution of salt (75 mg)

EXAMPLE 21

8-Fluoro-6- (trifluoromethyl) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 59 </formula> in water (10 mL) and CH 2 Cl (10 mL) was made basic (pH 10) using K 2 CO 3. The basic solution was extracted with CH 2 Cl 2 (10 mL) and the organic layer was dried over Na 2 SO 4, filtered and evaporated. The residue was triturated with hexanes to afford the title compound (67 mg, 0.24 mmol) as a white solid: 1 H NMR (300 MHz, CD 3 OD 7.29 (d, J = 10.2 Hz, 1H), 7 , 11-7.07 (m, 1H), 3.99-3.96 (m, 2H), 3.18-3.14 (m, 2H), 2.87-2.83 (m, 2H) 19 F {1 H} NMR (282 MHz, CD 3 OD? 61.1, -125.4; MS (APCI) 259.1 (M + H).

EXAMPLE 22

8-Methyl-6- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 60 </formula>

Step A. 1- (4-Methyl-2- (trifluoromethyl) phenyl) hydrazine hydrochloride was prepared as a white solid (220 mg, 0.97 mmol) following the procedure of example 14 Step A starting from 4-methyl-2- (trifluoromethyl) aniline (180 g, 1.0 mmol), sodium nitrite (83 mg, 1.2 mmol), SnCl 2 (418 mg, 2.2 mmol), 12 N HCl ( 2.5 mL + 0.8 mL), TFA (0.4 mL) and H2O (0.5 mL).

Step B. A resealable tube was charged with 1- (4-methyl-2- (trifluoromethyl) phenyl) hydrazine hydrochloride (156 mg, 0.69 mmol), 4-piperidone hydrochloride monohydrate (110 mg, 0.73 mmol) and IPA (2 mL). The solution was saturated with HCl gas, then the reaction tube was sealed. The reaction mixture was heated at 80 ° C for 18 h. The reaction mixture was cooled to room temperature and filtered. Analysis of the solid by reverse phase HPLC analysis indicated the presence of indole and hydrazone intermediate. Purification of the mixture by column chromatography did not significantly increase purity. A portion of this mixture (68 mg) was heated to reflux in THF (5 mL) and 2 N HCl (1 mL) overnight.

The suspension was filtered, washed with ether, then dried under vacuum to provide the target compound (38 mg, 0.13 mmol) as a white solid: mp338-342 ° C; 1H NMR (300 MHz1 CD3OD + DMSO-d6 δ 7.62 (br s, 1 H), 7.20 (br s, 1H), 4.47-4.46 (m, 2H), 3.65 (t , J = 6.2 Hz, 2H), 3.21 (t, J = 6.1 Hz, 2Η), 2.54 (s, 3 h); 19F (1H) NMR (282 MHz, CD3OD + DMS '). 0-cfe δ -62.0; MS (ESI) 255.1 (Μ + Η).

EXAMPLE 23

8-Methoxy-6- (trifluoromethyl) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 61 </formula>

Step A. 1- (4-Methoxy-2- (trifluoromethyl) phenyl) hydrazine hydrochloride was prepared as a pale pink solid (427 mg, 1.76 mmol) following the procedures. from Example 14 Step A starting from 4-methoxy-2- (trifluoromethyl) aniline (384 g, 1.0 mmol), sodium nitrite (170 mg, 1.2 mmol), SnCl 2 (840 mg, 2.2 mmol) 12 N HCl (5.0 mL + 1.5 mL), TFA (0.8 mL) and H2 O (10mL).

Step B. A microwave-sealable tube was charged with 1- (4-methoxy-2- (trifluoromethyl) phenyl) hydrazine hydrochloride (406 mg, 1.7 mmol), 4-piperidone hydrochloride monohydrate (268 mg, 1.7 mmol) eIPA (4 mL). The reaction mixture was saturated with HCl gas and the tube was sealed. The reaction mixture was subjected to microwave irradiation at 120 ° C for 12 min. The solid was filtered, washed with ether and treated with NaHCOssat. (10 mL). The basic solution was extracted with EtOAc (2 x 25 mL) and the combined organic extracts were dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification of the residue by column chromatography [silica gel, 5-75% (80: 18: 2 CHCl 3 Z MeOH ZNH 4 OH conc) ZCH 2 Cl 2] provided the target compound (192 mg, 0.71 mmol) as an off-white solid. mp 140-144 ° C; 1H NMR (300 MHz, CD3OD δ 7.10 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 3.97 (s, 2H), 3 , 83 (s, 3 h), 3.16 (t, J = 5.8 Hz, 2H), 2.87 (t, J = 5.7 Hz, 2H); 19F {1H} NMR (282 MHz, CD 3 OD δ -61.0; MS (ESI) 271 (M + H).

EXAMPLE 24

6-Chloro-8- (trifluoromethyl) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 61 </formula> To a suspension of 1- (2-chloro-4- (trifluoromethyl) phenyl) hydrazine (250 mg, 1.1mmol) and 4-piperidone hydrochloride monohydrate (183 mg 0.1 mmol) emIPA (3.5 mL) was bubbled with HCl (gas) for 10 min. The reaction mixture was sealed and then heated at 90 ° C for 15 h. The reaction mixture was cooled to 20 ° C, filtered and washed with ice cold IPA. The solid was dissolved in H 2 O, basified with 1 N NaOH to pH> 12 and extracted with CHGl 3. The combined organic solution was dried over MgSO 4, filtered and concentrated in vacuo to afford the title compound (42 mg, 0.15 mmol) as an off-white solid. MS (ES) 275.1 (M + H).

EXAMPLE 25

9-Methyl-6- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 62 </formula>

Step A. 1- (5-Methyl-2- (trifluoromethyl) phenyl) hydrazine hydrochloride was prepared as a white solid (3.0 g, 13.2 mmol) following the procedures of example 14 Step A starting from 5-methyl-2- (trifluoromethyl) aniline hydrochloride (2.8 g, 13.2 mmol), sodium nitrite (1.1 g, 15.9 mmol), SnCl2 (5.5 g, 29 mmol), 12 N HCl (30 mL + 8 mL), TFA (4.0 mL) and H2 O (4.2 mL).

Step Β. To a suspension of 1- (5-methyl-2- (trifluoromethyl) phenyl) hydrazine (3.5 g, 15.4 mmol) and 4-piperidone hydrochloride monohydrate (2.4 g, 15.4 mmol) in IPA ( 40 mL) was bubbled HCl (gas) for 10 min. The reaction mixture was sealed and then heated at 90 ° C for 36 h. The reaction mixture was cooled to 20 ° C, filtered and washed with ice cold IPA to afford the title compound (3.8 g, 13 mmol) as a pale yellow solid: MS (ES) 255.1 (M + H) .

EXAMPLE 26

6-Methyl-7- (trifluoromethyl) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride <formula> formula see original document page 63 </formula>

To a suspension of 1- (2-methyl-3- (trifluoromethyl) phenyl) hydrazine (520 mg, 2.3 mmol) and 4-piperidone hydrochloride monohydrate (353 mg, 2.3 mmol) in IPA (6.4 mL) ) HCl (gas) was bubbled for 10 min. The reaction mixture was sealed and then heated at 90 ° C for 15 h. The reaction mixture was cooled to 20 ° C, filtered and washed with ice cold IPA to afford the title compound (455 mg, 1.6 mmol) as an off-white solid: MS (ES) 255.1 (M + H ).

Example 27

8-Bromo-6-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 63 </formula>

Step A. A solution of sodium nitrite (0.70 g, 10.2 mmol) and H 2 O (2.1 mL) was added dropwise at 0 ° C to a 4-bromo-2-ethylbenzenamine hydrochloride solution (2 0.1 g, 8.45 mmol) in 12 N HCl (20.1 mL) and TFA (2.6 mL). The reaction mixture was stirred at 0 ° C for 1 h followed by the dropwise addition of a solution of tin (II) chloride (3.53 g, 18.6 mmol) in 12 N HCl (5.0 mL) and H 2 O (0.7 mL) at 0 ° C. The reaction mixture was stirred for 15 h at 20 ° C and was filtered to afford 1- (4-bromo-2-ethylphenyl) hydrazine hydrochloride as an off-white solid (2.9 g, 11.5 mmol). .

Step B. A solution of 1- (4-bromo-2-ethylphenyl) hydrazine hydrochloride (0.25g, 1.0 mmol), 4-piperidone hydrochloride monohydrate (0.15 g, 1.0 mmol) and 12 N (0.25 mL, 3.0 mmol) in EtOH (3.0 mL) was stirred at 85 ° C for 90min. The reaction mixture was filtered and washed with ice cold EtOH to obtain the title compound (0.12g, 0.37 mmol) as a white solid: MS (ES) 279.0 (M + H).

EXAMPLE 28

9-Chloro-6-methylsulfanyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 64 </formula>

Step A. A solution of sodium nitrite (2.38 g, 34.6 mmol) and H 2 O (2.28 mL) was added dropwise at 0 ° C to a solution of 5-chloro-2- (methylthio) benzenamine (5%). 0 g, 28.8 mmol) in 12 N HCl (68.6 mL) and TFA (8.7 mL). The reaction mixture was stirred at 0 ° C for 1 h followed by the addition of an excess of tin chloride solution. (II) (12.0 g, 63.4 mmol) in 12 N HCl (17.2 mL) and H 2 O (2.3 mL) at 0 ° C. The reaction mixture was stirred for 15 h at 20 ° C and was filtered to afford 1- (5-chloro-2- (methylthio) phenyl) hydrazine hydrochloride as a white solid.

Step B. A solution of 1- (5-chloro-2- (methylthio) phenyl) hydrazine hydrochloride (0.80 g, 3.55 mmol) and 4-piperidone hydrochloride monohydrate (0.55 g, 3.55 mmoles) in EtOH (10 mL) was reacted in a microwave reactor at 180 ° C for 30 min. The reaction mixture was filtered to obtain the title compound (0.63 g, 2.18 mmol): MS (ES) 253.01 (M + H).

EXAMPLE 29

6-MetHsulfanyl-9-trifluoromethyl-2,3A5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 64 </formula>

Step A. A solution of sodium nitrite (1.8 g, 25.9 mmol) and H 2 O (5.4 mL) was added dropwise at 0 ° C to a solution of 2-chloro-5-methylbenzenamine (4.5 g, 21.6 mmol) in 12 N HCl (51.4 mL) and TFA (6.5 mL). The reaction mixture was stirred at 0 ° C for 1 h followed by the dropwise addition of a solution of tin (II) chloride (9.0 g, 47.5 mmol) in 12 N HCl (12.9 mL) and H 2 O (1 , 7 mL) at 0 ° C. The reaction mixture was stirred 15 h at 20 ° C and was filtered to afford 1- (2-chloro-5-methylphenyl) hydrazine hydrochloride as an off-white solid (5.19 g, 20.0 mmol).

Step B. A solution of 1- (2-chloro-5-methylphenyl) hydrazine hydrochloride (0.17 g, 0.67 mmol), 4-piperidone hydrochloride monohydrate (0.10 g, 0.67 mmol) and HCl NaCl (0.17 mL, 2.0 mmol) in EtOH (2.0 mL) was reacted in a microwave oven at 185 ° C for 30 min. The reaction mixture was filtered and washed with ice cold EtOH to obtain the title compound (50.5mg, 0.16 mmol): MS (ES) 287.14 (M + H).

Example 30

7-Chloro-6-methylsulfanyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 65 </formula>

Step A. 1- (3-Chloro-2- (methylthio) phenyl) hydrazine hydrochloride was prepared as a white solid (15.1 g, 67 mmol) following the procedures of example 14 Step A starting from 3 -chloro-2- (methylthio) benzenamine (11.6 g, 67.1 mmol), sodium nitrite (5.6 g, 67 mmol), SnCl 2 (25.4 g, 134 mmol), 12 N HCl (242 mL + 121 mL) and H 2 O (10 mL).

Step Β. The mixture of 1- (3-chloro-2- (methylthio) phenyl) hydrazine hydrochloride (15.1 g, 67 mmol) and 4-piperidone hydrochloride monohydrate (10.3 mg, 67 mmol) in CF 3 CH 2 OH (300 mL) was refluxed for 30 min. To the reaction mixture was added 12 N HCl (5 mL, 60 mmol). The reaction mixture was refluxed for 15 h, cooled to 20 ° C, filtered and CFaCH2 OH washed to give the title compound (16.4 g, 58 mmol) as a white solid: MS (ES) 253, 1 (M + H).

EXAMPLE 31

7-Bromo-6- (3-chloropropylthio) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride <formula> formula see original document page 66 </formula>

Step A. To a solution of 1-bromo-2-chloro-3-nitrobenzene (750 mg, 3.2 mmol) and 3-chloropropane-1-thiol (354 mg, 3.2 mmol) in THF (6.4 mL ) was added KOH (270 mg, 4.8 mmol). The reaction mixture was heated at 45 ° C for 3 days and cooled to 20 ° C. The reaction mixture was chromatographed on silica gel to afford (2-bromo-6-nitrophenyl) (3-chloropropyl) sulfane (714 mg, 2.3 mmol).

Step Β. To a solution of (2-bromo-6-nitrophenyl) (3-chloropropyl) sulfane (714mg, 2.3 mmol) in MeOH (10 mL) was added Pd (OH) 2 (20%, 100 mg). The reaction mixture was stirred for 3 days under 0.34 MPa H2 ((349.1 KPa50 psi)) for 3 days and then filtered. The filtrate was concentrated in vacuo and the residue was dissolved in Et 2 O. To the solution was added excess HCl (1M in Et 2 O) to form a white precipitate. The solid was filtered and washed with Et 2 O to afford 3-bromo-2- (3-chloropropylthio) benzenamine (646 mg, 2.3 mmol).

Step C. 1- (3-Bromo-2- (3-chloropropylthio) phenyl) hydrazine hydrochloride (672mg, 2.0 mmol) was prepared as a white solid following the procedures of example 14 Step A starting from 3- bromo-2- (3-chloropropylthio) benzenamine (646 mg, 2.3 mmol), sodium nitrite (190 mg, 2.7 mmol), SnCl 2 (960 mg, 5.1 mmol), 12 N HCl (5 3 mL + 1.5 mL) and H2 O (0.8 mL).

Step D. The mixture of 1- (3-bromo-2- (3-chloropropylthio) phenyl) hydrazine hydrochloride (500 mg, 1.5 mmol) and 4-piperidone hydrochloride monohydrate (230mg, 1.5 mmol ) in CF 3 CH 2 OH (4 mL) was heated at 80 ° C for 30 min. To the reaction mixture was added 12 N HCl (0.3 mL). The reaction mixture was heated at 80 ° C for 5 h, cooled to 20 ° C, filtered and washed with IPA to afford the title compound (549 mg, 1.4 mmol) as a white solid: MS (ES). 359.0 (M + H).

EXAMPLE 32 6- (3-Chloropropylthio) -9-fluoro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 67 </formula>

Step A. (3-Chloropropyl) (4-fluoro-2-nitrophenyl) sulfane (1.3 g, 5.2 mmol) was prepared following the procedures of example 31 Step A starting from 1,4-difluoro-2-nitrobenzene ( 980 mg, 6.15 mmol), 3-chloropropane-1-thiol (680mg, 6.15 mmol), KOH (517 mg, 9.2 mmol) and THF (13 mL).

Step Β. 2- (3-Chloropropylthio) -5-fluorobenzenamine hydrochloride (1.26 g, 4.9 mmol) was prepared following the procedures of example 31 Step B starting from (3-chloropropyl) (4-fluoro-2-nitrophenyl) sulfane (1.3 g, 5.2 mmol), Pd (OH) 2 (20%, 200 mg) and MeOH (20 mL).

Step C. 1- (2- (3-Chloropropylthio) -5-fluorophenyl) hydrazine hydrochloride (1.25g, 4.6 mmol) was prepared as a white solid following the procedures of example 14 Step A starting from 2- (3-chloropropylthio) -5-fluorobenzenamine hydrochloride (1.26 g, 4.9 mmol), sodium nitrite (380 mg, 5.5 mmol), SnCl 2 (1.92 g, 10.1 mmol), 12 N HCl (12 mL + 3.0 mL) and H 2 O (1.6 mL).

Step D. The mixture of 1- (2- (3-chloropropylthio) -5-fluorophenyl) hydrazine hydrochloride (1.25 g, 4.6 mmol) and 4-piperidone hydrochloride monohydrate (707mg, 4.6 mmol) in CF 3 CH 2 OH (14 mL) was refluxed for 2h. To the reaction mixture was added 12 N HCl (0.8 mL, 9.6 mmol). Reaction mixture was refluxed for 15 h, cooled to 20 ° C, filtered and washed with CF 3 CH 2 OH to afford the title compound (1.07 g, 3.2 mmol) as a white solid: MS (ES) 299 0.1 (M + H).

Example 33

7-Chloro-6- (3-chloropropylthio) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride <formula> formula see original document page 68 </formula>

Step A. (2-Chloro-6-nitrophenyl) (3-chloropropyl) sulfane (1.09 g, 4.1 mmol) was prepared following the procedures of example 31 Step A from 1,2-dichloro-3-nitrobenzene (1.12 g, 5.9 mmol), 3-chloropropane-1-thiol (652 mg, 5.9 mmol), KOH (517 mg, 9.2 mmol) and THF (13 mL).

Step Β. 3-Chloro-2- (3-chloropropylthio) benzenamine hydrochloride (845 mg, 3.1 mmol) was prepared following the procedures of example 31 Step B starting from (2-chloro-6-nitrophenyl) (3-chloropropyl) sulfane (1.09 g, 4.1 mmol) (20%, 180 mg) and MeOH (18 mL).

Step C. 1- (3-Chloro-2- (3-chloropropylthio) phenyl) hydrazine hydrochloride (877mg, 3.05 mmol) was prepared as a white solid following the procedures of Example 14 Step A starting from the 3-chloro-2- (3-chloropropylthio) benzenamine (845 mg, 3.1 mmol), sodium nitrite (255 mg, 3.7 mmol), SnCl 2 (1.29 g, 6.8 mmol), HCl a 12 N (8 mL + 2.0 mL) and H 2 O (1.2 mL).

Step D. The mixture of 1- (3-chloro-2- (3-chloropropylthio) phenyl) hydrazine hydrochloride (877 mg, 3.05 mmol) and 4-piperidone hydrochloride monohydrate (469 mg, 3.05 mmol) ) in CF 3 CH 2 OH (8 mL) was refluxed for 2h. To the reaction mixture was added 12 N HCl (0.8 mL, 9.6 mmol). The reaction mixture was refluxed for 24 h, cooled to 20 ° C, filtered and washed with CF 3 CH 2 OH to afford the title compound (879mg, 2.5 mmol) as a white solid: MS (ES) 315.0 ( M + H).

EXAMPLE 34

9-Bromo-6- (3-chloropropylthio) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride <formula> formula see original document page 69 </formula>

Step A. (4-Bromo-2-nitrophenyl) (3-chloropropyl) sulfane (1.5 g, 4.8 mmol) was prepared following the procedures of example 31 Step A from 1,4-dibromo-2-nitrobenzene (1.73 g, 6.15 mmol), 3-chloropropane-1-thiol (680 mg, 6.15 mmol), KOH (517 mg, 9.2 mmol) and THF (13 mL).

Step B. 5-Bromo-2- (3-chloropropylthio) benzenamine hydrochloride (1.14 g, 3.6 mmol) was prepared following the procedures of example 31 Step B starting from (4-bromo-2-nitrophenyl) ( 3-chloropropyl) sulfane (1.4 g, 4.5 mmol), Pd (OH) 2 (20%, 200 mg) and MeOH (20 mL).

Step C. 1- (5-Bromo-2- (3-chloropropylthio) phenyl) hydrazine hydrochloride (1.19g, 3.6mmol) was prepared as a white solid following the procedures of example 14 Step A starting from 5-bromo-2- (3-chloropropylthio) benzenamine hydrochloride (1.14 g, 3.6 mmol), sodium nitrite (298 mg, 4.3 mmol), SnCl 2 (1.33 g, 7.0 mmol) ), 12 N HCl (8.2 mL + 2.2 mL) and H2 O (1.2 mL).

Step D. The mixture of 1- (5-bromo-2- (3-chloropropylthio) phenyl) hydrazine hydrochloride (1.19 g, 3.6 mmol) and 4-piperidone hydrochloride monohydrate (553 mg, 3 , 6 mmol) in CF 3 CH 2 OH (10 mL) was refluxed for 3 h. To the reaction mixture was added 12 N HCl (0.6 mL, 7.2 mmol). The reaction mixture was refluxed for 15 h, cooled to 20 ° C, filtered and washed with CF 3 CH 2 OH to afford the title compound (927 mg, 2.3 mmol) as a white solid: MS (ES) 359.0 (M + H).

EXAMPLE 35

6- (3-Chloropropylthio) -9-nitro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride <formula> formula see original document page 70 </formula>

Step A. To a solution of 2-fluoro-5-nitrobenzenamine (500 mg, 3.2 mmol) and 3-chloropropane-1-thiol (354 mg, 3.2 mmol) in DME (6.4 mL) KOH (270 mg, 4.8 mmol) was added. The reaction mixture was heated at 450 ° C for 3 days and cooled to 20 ° C. The reaction mixture was subjected to silica gel chromatography (3% MeOH / CH 2 Cl 2) to afford 2- (3-chloropropylthio) -5-nitrobenzenamine (130 mg, 0.53 mmol).

Step Β. 1- (2- (3-Chloropropylthio) -5-nitrophenyl) hydrazine hydrochloride (100mg, 0.34 mmol) was prepared as a white solid following the procedures of example 14 Step A starting from 2- (3-chloropropylthio) ) -5-nitrobenzenamine (100 mg, 0.44 mmol), sodium nitrite (34 mg, 0.49 mmol), SnCl 2 (156 mg, 0.82 mmol), 12 N HCl (1.5 mL) and H 2 O (0.1 mL).

Step C. The mixture of 1- (2- (3-chloropropylthio) -5-nitrophenyl) hydrazine hydrochloride (100 mg, 0.34 mmol) and 4-piperidone hydrochloride monohydrate (58mg, 0.38 mmol) in CF 3 CH 2 OH (1 mL) was heated at 87 ° C for 30 min.

To the reaction mixture was added 12 N HCl (3 mL). The reaction mixture was refluxed for 1 h, cooled to 20 ° C, filtered and washed with IPA to afford the title compound (78 mg, 0.24 mmol) as a white solid: MS (ES) 326.1 (M + H).

Step A. (4-Methoxy-2-nitro-phenyl) -hydrazine hydrochloride (560 mg, 2.55mmoles) was prepared as a white solid following the procedures of example 14 Step A starting from 4-methoxy -2-nitrobenzenamine (525 mg, 3.1 mmol), sodium nitrite (235 mg, 3.4 mmol), SnCl 2 (1.06 g,

Example 36

8-Methoxy-6-nitro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 70 </formula> 5.6 mmol), 12 N HCl (6.5 mL) and H2O (1.0 mL).

Step Β. The title compound (220 mg, 0.89 mmol) was prepared as a yellow solid following the procedures of example 34. Step C Followed by basic work-up starting from (4-methoxy-2-nitro-phenyl) -hydrazine hydrochloride (560 mg, 2.55 mmol) and 4-piperidone hydrochloride monohydrate (400 mg, 2.6 mmol) in CF 3 CH 2 OH (7 mL): MS (ES) 248.1 (M + H).

Step A. 1- (2-Bromo-5-nitrophenyl) hydrazine (650 mg, 2.43 mmol) was prepared as a white solid following the procedures of example 14 Step A starting from 2-bromo -5-nitrobenzenamine (651 mg, 3.0 mmol), sodium nitrite (250 mg, 3.6 mmol), SnCl 2 (1.25 g, 6.6 mmol), 12 N HCl (7.5 mL) ) and H 2 O (1.1 mL).

Step Β. The title compound (215 mg, 0.73 mmol) was prepared as a yellow solid following the procedures of example 34. Step C Followed by basic work up starting from 1- (2-bromo-5-nitrophenyl) hydrazine (650 mg 2, 43 mmol) and 4-piperidone hydrochloride monohydrate (373 mg, 2.43 mmol) in CF 3 CH 2 OH (7 mL): MS (ES) 296.0 (M + H).

Example 38

7-Chloro-6- (p-tolylthio) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 71 </formula>

Step A. 1- (3-Chloro-2- (p-tolylthio) phenyl) hydrazine hydrochloride (253 mg, 0.85mmol) was prepared following the procedures of example 14 Step A starting from 3-chloro-2 - (p-tolylthio) benzenaminà (250 mg, 1.0 mmol), sodium nitrite

Example 37

6-Bromo-9-nitro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 71 </formula> indium (82 mg, 1.2 mmol), SnCl 2 (372 mg, 1.9 mmol), 12 N HCl (4.0 mL + 1.5 mL) and H 2 O (0.4 mL).

Step Β. The mixture of 1- (3-chloro-2- (p-tolylthio) phenyl) hydrazine hydrochloride (85mg, 0.28mmol) and 4-piperidone hydrochloride monohydrate (44mg, 0.28mmol) in CF 3 CH 2 OH (1, 0 mL) was heated at 80 ° C for 15 h, cooled to 20 ° C, filtered and washed with IPA to afford the title compound (61mg, 0.17 mmol) as a light brown solid: MS (ES) 329, 1 (M + H).

Example 39

6- (4-Chlorophenylthio) -9- (trifluoromethyl) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 72 </formula>

Step A. 1- (2- (4-Chlorophenylthio) -5- (trifluoromethyl) phenyl) hydrazine hydrochloride (468 mg, 1.3 mmol) was prepared following the procedures of example 14. Step A starting from 2- (4- chlorophenylthio) -5- (trifluoromethyl) benzenamine (500mg, 1.7mmol), sodium nitrite (141mg, 2.1mmol), SnCl 2 (646mg, 3.4mmol), 12 N HCl (6.8ml) + 2.5 mL) and H 2 O (0.7 mL).

Step Β. The title compound (114 mg, 0.27 mmol) was prepared following the procedure of example 38 step B starting from 1- (2- (4-chlorophenylthio) -5- (trifluoromethyl) phenyl) hydrazine hydrochloride (150 mg, 0 4-piperidone hydrochloride monohydrate (65 mg, 0.42 mmol) and CF 3 CH 2 OH (1.5 mL) as a light orange solid: MS (ES) 383.1 (M + H) .

Example 40

9-Chloro-6- (4-chlorophenylthio) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride <formula> formula see original document page 73 </formula>

Step A. 1- (5-Chloro-2- (4-chlorophenylthio) phenyl) hydrazine hydrochloride (452 mg, 1.4 mmol) was prepared following the procedures of example 14 Step Starting from 5-chloro-2- ( 4-chlorophenylthio) benzenamine (400 mg, 1.5 mmol), sodium nitrite (125 mg, 1.8 mmol), SnCl 2 (570 mg, 3.0 mmol), 12 N HCl (5.0 mL) + 2.5 mL) and H 2 O (0.7 mL).

Step Β. The title compound (97 mg, 0.25 mmol) was prepared following the procedure of example 38 step B starting from 1- (5-chloro-2- (4-chlorophenylthio) phenyl) hydrazine hydrochloride (150 mg, 0.47 mmol), 4-piperidone hydrochloride monohydrate (72 mg, 0.47 mmol) and CF 3 CH 2 OH (1.0 mL) as a light brown solid: MS (ES) 349.0 (M + H).

EXAMPLE 41

7-Methyl-6- (p-tolylthio) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 73 </formula>

Step A. A mixture of 2-chloro-1-methyl-3-nitrobenzene (2.75 g, 16.1 mmol), 4-methylbenzenethiol (2.0 g, 16.1 mmol), NaH (968 mg ( 60%), 24.2) in anhydrous THF (30 mL) was stirred for 24 h at 20 ° C. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford crude (2-methyl-6-nitrophenyl) (p-tolyl) sulfane (3.8 g, 14.7 mmol) which was used directly for the subsequent step.

Step Β. 3-Methyl-2- (p-tolylthio) benzenamine hydrochloride (380 mg, 1.43mmol) was prepared following the procedures of example 31 Step B starting from (2-methyl-6-nitrophenyl) (p-tolyl ) sulfane (518 mg, 2.0 mmol), Pd (OH) 2 (20%, 125 mg) and EtOH (100 mL).

Step C. 1- (3-Methyl-2- (p-tolylthio) phenyl) hydrazine hydrochloride (308 mg, 1.1mmol) was prepared as a white solid following the procedures of example 14 Step A starting from 3-methyl-2- (p-tolylthio) benzeneamine hydrochloride (380 mg, 1.43 mmol), sodium nitrite (148 mg, 2.2 mmol), SnCl 2 (545 mg, 2.9 mmol) 12 N HCl (5.0 mL + 2.5 mL) and H 2 O (0.7 mL).

Step D. The mixture of 1- (3-methyl-2- (p-tolylthio) phenyl) hydrazine hydrochloride (308 mg, 1.1 mmol) and 4-piperidone hydrochloride monohydrate (169 mg, 1.1 mmol) in CF 3 CH 2 OH (4 mL) was refluxed for 1 h. To the reaction mixture was added 12 N HCl (1.5 mL, 18 mmol). The reaction mixture was refluxed for 15 h, cooled to 20 ° C, filtered and washed with Et 2 O to afford the title compound (152 mg, 0.44 mmol) as an off-white solid: MS (ES ) 309.1 (M + H).

EXAMPLE 42

8-Bromo-9-chloro-6-methyl-2,3,4s5-tetrahydro-1H-pyrido [4,3-b] indole

<formula> formula see original document page 74 </formula>

Step A. To a solution of 9-chloro-6-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (0.47 g, 1.8 mmol) in THF ( 7.3 mL) Et 3 SiH (1.1 g, 9.1 mmol) was added at 20 ° C and stirred for 18 h. The reaction mixture was concentrated in vacuo and washed with hexanes to obtain eis-9-chloro-6-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4.3 -b] indole (1.1 g, 3.3 mmol). Step Β. To a solution of c / s-9-chloro-6-methyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole (1.1 g, 3.2 mmoles) and di-tert-butyl dicarbonate (0.76 g, 3.5 mmol) in 1,4-dioxane (30.0 mL) was added 1 N NaOH (9.4 mL, 9.4 mmol) at 20 ° C and stirred for 3 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in diethyl ether, washed with brine, dried over MgSO 4, filtered and concentrated in vacuo to afford c / s-9-chloro acid ester. -6-methyl-1,3,4,4a, 5,9b-hexahydro-pyrido [4,3-b] indole-2-carboxylic acid (0.81 g, 1.5 mmol).

Step C. To a solution of eis-9-chloro-6-methyl-1,3,4,4a, 5,9b-hexahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.2g, 0.62 mmol) in DMF (1 mL) was added a solution of NBS (0.08 g, 0.50 mmol) in DMF (0.6 mL) in drops at 0 ° C. The reaction mixture was stirred for 30min at 0 ° C, then quenched with H 2 O and extracted with diethyl ether. The combined organic solution was washed with 1 N NaOH, brine and dried over MgSO 4, filtered and concentrated in vacuo. The residue was subjected to silica gel column chromatography (70% Hex / EtOAc) to give c / s-8-bromo-9-chloro-6-methyl-1,3-acid ester. 4,4a, 5,9b-hexahydro-pyrido [4,3-b] indole-2-carboxylic acid (0.16 g, 0.4 mmol).

Step D. To a degassed solution of eis-8-bromo-9-chloro-6-methyl-1,3,4,4a, 5,9b-hexahydro-pyrido [4,3-b] tert-butyl ester indol-2-carboxylic acid (48.3 mg, 0.12 mmol) and potassium carbonate (49.8 mg, 0.36 mmol) in DMF (2.4 mL) was added diethyl zinc (0.22 mL, 0 mL). 24 mmol) and [1, V-Bis (di-phenylphosphino) ferrocene] dichloropalladium (4.9 mg, 6.0 μηποίβε). The reaction mixture was stirred at 80 ° C for 15 h followed by dilution with diethyl ether and extraction with H 2 O. The combined organic solution was washed with H2 O and brine, dried over MgSO4, filtered and concentrated in vacuo to obtain a mixture of recovered starting material and oxidation product. To this obtained mixture (44.2 mg, 0.11 mmol) at 20 ° C was added 20% TFA / CH 2 Cl 2 (0.93 mL) and stirred for 30 min, concentrated in vacuo to an amber oil (62.4 mg, 0.21 mmol), which was purified by HPLC (MeOH / H2 O) to obtain the title compound (4.9 mg, 0.02 mmol): MS (ES) 299.1 (M + H).

Example 43

6-Chloro-8-fluoro-9-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 75 </formula>

Step A. A solution of sodium nitrite (1.1 g, 15.9 mmol) and H 2 O (3.3 mL) was added dropwise at 0 ° C to a solution of 2-chloro-4-fluoro-5-methylbenzenamine (2 0.1 g, 13.2 mmol) in 12 N HCl (31.4 mL) and TFA (4.0 mL). The reaction mixture was stirred at 0 ° C for 1 h followed by the dropwise addition of a solution of tin (II) chloride (5.5 g, 29.1 mmol) in 12 N HCl (7.9 mL) and H 2 O (1.0 mL) at 0 ° C. The reaction mixture was stirred for 15 h at 20 ° C and was filtered to afford 1- (2-chloro-4-fluoro-5-methylphenyl) hydrazine hydrochloride (2.7 g, 12.8 mmol).

Step B. A solution of 1- (2-chloro-4-fluoro-5-methylphenyl) hydrazine (0.49 g, 2.8 mmol) and 4-piperidone hydrochloride monohydrate (0.43 g, 2.8 mmol) in TFE (1.14 mL) was stirred at 65 ° C for 15 h to form 1- (2-chloro-4-fluoro-5-methylphenyl) -2- (piperidin-4-ylidene) hydrazine hydrochloride, observed by LCMS: MS (ES) 256.22 (M + H). The reaction mixture was stirred at 65 ° C for an additional 15 h after the addition of 12 N HCl (0.7 mL, 8.4 mmol). The reaction mixture was cooled and filtered to obtain the title compound as a beige solid (0.49 g, 1.8 mmol): MS (ES) 239.2 (M + H).

EXAMPLE 44

6,8,9-Trichloro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride

<formula> formula see original document page 76 </formula>

Step A. A solution of sodium nitrite (0.91 g, 13.2 mmol) and H 2 O (2.7 mL) was added dropwise at 0 ° C to a solution of 2,4,5-trichlorobenzenamine (2.2 mL). g, 11.0 mmol) in 12 N HCl (26.3 mL) and TFA (3.3 mL). The reaction mixture was stirred at 0 ° C for 1 h followed by the dropwise addition of a solution of tin (II) chloride (4.6 g, 24.3 mmol) in 12 N HCl (6 6 mL) and H 2 O (0.9 mL) at 0 ° C. The reaction mixture was stirred for 15 h at 20 ° C and was filtered to afford 1- (2,4,5-trichlorophenyl) hydrazine hydrochloride (2.4 g, 9.7 mmol).

Step B. A solution of 1- (2,4,5-trichlorophenyl) hydrazine hydrochloride (1.0 g, 4.0 mmol) and 4-piperidone hydrochloride monohydrate (0.62 g, 4.0 mmol) ) in EtOH (11.9 mL) was stirred at 75 ° C for 3.5 h, cooled to 20 ° C and filtered to give 1- (piperidin-4-ylidene) -2- (2,4,5- trichlorophenyl) hydrazine as an off-white solid (0.74 g, 2.3 mmol).

Step C. 12 N HCl (0.2 mL, 2.3 mmol) was added to a solution of 1- (piperidin-4-ylidene) -2- (2,4,5-trichlorophenyl) hydrazine hydrochloride (0 25 g, 0.76 mmol) in TFE (2.2 mL) and was reacted in a microwave reactor at 170 ° C for 30 min. The reaction mixture was cooled and filtered to obtain the title compound (97.3 mg, 0.31 mmol) as a solid brown: MS (ES) 275.08 (M + H).

EXAMPLE 45

6,7-Dichloro-5-methyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 77 </formula>

Step A. To a solution of 6,7-dichloro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrotri-fluoroacetate (180 mg, 0.53 mmol) and dicarbonate of Di-tert-butyl (128 mg, 0.59 mmol) in 1,4-dioxane (5.0 mL) was added 1N NaOH (1.6 mL, 1.6 mmol) at 20 ° C and stirred for 5 min. H. The reaction mixture was concentrated in vacuo and the residue was extracted with Et 2 O. The combined organic layer was washed successively with H 2 O, 1 N HCl, H 2 O, sat. Aq. and brine. The organic phase was dried over MgSO 4, filtered and vacuum concentrated to obtain 6,7-dichloro-1,3,4,5-tetrahydro-pyrido [4,3-b] indol-2-tert-butyl ester. carboxylic acid (183 mg, 0.53 mmol) as an off-white solid.

Step Β. To a solution of 6,7-dichloro-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (183 g, 0.53 mmol) in DME (3.0mL) was added triturated KOH (150 mg, 2.7 mmol) and Mel (753 g, 5.3 mmol) at 20 ° C. The reaction mixture was stirred at 95 ° C for 3 h, cooled, diluted with H 2 O and extracted with diethyl ether. The combined organic solution was washed with H 2 O and brine, dried over MgSO 4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (Hex / EtOAc 9/1) to obtain 6,7-dichloro-5-methyl-1,3,4,5-tetrahydro-pyrido acid tert-butyl ester [ 4,3-b] indole-2-carboxylic acid (133 mg, 0.37 mmol) as a light yellow solid.

Step C. To a solution of 6,7-dichloro-5-methyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (130 mg, 0.37 mmol) in CH 2 Cl 2 (2.0 mL) was added TFA (0.4 mL). The reaction mixture was stirred for 1 h at 20 ° C, then concentrated in vacuo. The residue was dissolved in H2 O and basified with 1 N NaOH to pH> 12, extracted with CHCl3. The combined organic solution was dried over MgSO 4, filtered and concentrated in vacuo to obtain the title compound (82 mg, 0.32 mmol) as a light brown solid: MS (ES) 255.1 (M + H) .

EXAMPLE 46

5,6,8-Trimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 78 </formula>

Step A. To a solution of 6,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (0.39 g, 1.6 mmol) and dicarbonate of Di-t-butyl (0.39 g, 1.8 mmol) in 1,4-dioxane (15.6 mL) was added 1 N NaOH (4.9 mL, 4.9 mmol) at 20 ° C. and stirred for 5 h. The reaction mixture was concentrated in vacuo, the residue was solubilized in EtOAc, Et 2 O and H 2 O, the organic phase was washed with H 2 O, 1 N HCl, H 2 O, aq. of sat. and stressed it out. The organic phase was dried over MgSO 4, filtered and concentrated in vacuo to afford 6,8-dimethyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indol-2-tert-butyl ester. carboxylic acid as a yellow solid (0.40g, 1.34mmol).

Step Β. To a solution of 6,8-dimethyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.37 g, 1.2 mmol) In DME (6.9mL) was added crushed KOH (0.34g, 6.1mmol) and Mel (1.7g, 12.2mmol) at 20 ° C. The reaction mixture was stirred at 85 ° C for 30 min, cooled, diluted with H 2 O and extracted with diethyl ether. The combined organic solution was washed with H 2 O and brine and dried over MgSO 4, filtered and concentrated in vacuo. The residue was subjected to silica gel column chromatography (95-90% gradient Hex / EtOAc) to obtain 5,6,8-trimethyl-1,3,4,5-tetrahydroxy acid tert-butyl ester. pyrido [4,3-b] indol-2-carboxylic acid (0.29 g, 0.76 mmol) as a white solid.

Step C. To 5,6,8-trimethyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.29 g, 0.75 mmol) at 0 ° C was added 20% TFA / CH 2 Cl 2 (7.9 mL) and stirred for 80 min. Stirred for an additional 1 h at 20 ° C, concentrated in vacuo to a brown solid (0.4 g, 1.0 mmol), of which 175.0 mg was purified by HPLC (MeOH / H2 O) to obtain the title compound (108, 7 mg, 0.3 mmol): MS (ES) 215.2 (M + H).

EXAMPLE 47

9-Chloro-5,6-dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 79 </formula>

Step A. To a solution of 9-chloro-6-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (0.2 g, 0.78 mmol) and dicarbonate of Di-tert-butyl (0.19 g, 0.9 mmol) in 1,4-dioxane (7.4 mL) was added 1 N NaOH (2.3 mL, 2.3 mmol) at 20 ° C and stirred. for 3.5 h. The reaction mixture was concentrated in vacuo, the residue was solubilized in EtOAc, Et2O and H2O, the organic phase was washed with H2O, 1N HCl, H2O1 aq. of sat. and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford 9-chloro-6-methyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indol-2 tert-butyl ester. -carboxylic as a yellow solid (0.24g, 0.76 mmol).

Step Β. To a solution of 9-chloro-6-methyl--1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.24 g, 0, 76 mmol) in -DME (4.3 mL) was added triturated KOH (0.21 g, 3.8 mmol) and Mel (1.1g, 7.6 mmol) at 20 ° C. The reaction mixture was stirred at 85 ° C for 4 h, cooled, diluted with H 2 O and extracted with Et 2 O. The combined organic solution was washed with H 2 O and brine and dried over MgSO 4, filtered and concentrated in vacuo to obtain 9-chloro-5,6-dimethyl-1,3,4-acid tert-butyl ester. 5-Tetrahydro-pyrido [4,3-b] indol-2-carboxylic acid as a pale yellow solid (0.25, 0.73 mmol).

Step C. To 9-Chloro-5,6-dimethyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.25 g, 0 0.73 mmol) at 0 ° C was added 20% TFA / CH 2 Cl 2 (7.7 mL) and stirred for 10 min. Stirred for an additional 50 min at 20 ° C, concentrated in vacuo to a brown solid (0.34 g, 0.98 mmol) of which 154.0 mg was purified by HPLC (CH 3 CN / H 2 O) to obtain the title compound ( 68.7 mg, 0.20 mmol): MS (ES) 235.2 (M + H).

EXAMPLE 48

5,7,9-Trimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 80 </formula>

Step A. To a solution of 7,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (0.2 g, 0.85 mmol) and di-dicarbonate. tert-Butyl (0.20 g, 0.93 mmol) in 1,4-dioxane (8.1 mL) was added 1 N NaOH (2.5 mL, 2.5 mmol) at 20 ° C and stirred for 2 H. The reaction mixture was concentrated in vacuo, the residue was solubilized in EtOAc, Et2O and H2O, the organic phase was washed with H2O, 1 N HCl, H2O, aq. of sat. NaHCO 3, H 2 O and brine. The organic phase was dried over MgSO 4, filtered and concentrated in vacuo to afford 7,9-dimethyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indol-2-yl ester. 2-carboxylic acid (0.24g, 0.76 mmol) as a white solid.

Step Β. To a solution of 7,9-dimethyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.23 g, 0.75 mmol) in DME (4.3mL) was added crushed KOH (0.21g, 3.8mmol) and Mel (1.1g, 7.6mmol) at 20 ° C. The reaction mixture was stirred at 85 ° C for 4.5 h, cooled, diluted with H 2 O and extracted with Et 2 O. The combined organic solution was washed with H2O and brine and dried over MgSO4, filtered and concentrated in vacuo to give 5,7,9-trimethyl-1,3,4,5-tetrahydro-pyrido acid tert-butyl ester [4, 3-b] indole-2-carboxylic acid (0.24, 0.75 mmol) as a pale yellow solid.

Step C. 5,7,9-Trimethyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.24 g, 0.75 mmol) at 0 ° C was added 20% TFA / CH 2 Cl 2 (7.9 mL) and stirred for 10 min. Stirred for an additional 50 min at 20 ° C, concentrated in vacuo to a brown solid (0.41g, 1.2 mmol), of which 217.0 mg was purified by HPLC (CH 3 CN / H 2 O) to obtain the title compound ( 91.7 mg, 0.28 mmol): MS (ES) 215.3 (Μ + Η).

Example 49

9-Fluoro-5,6-dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 81 </formula>

Step A. To a solution of 9-Fluoro-6-methyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride (0.2 g, 0.7 mmol) and di-tert-butyl dicarbonate (0.17 g, 0.8 mmol) in 1,4-dioxane (6.9 mL) was added 1 N NaOH (2.2 mL, 2.2 mmol) at 20 °. G is stirred for 1 h. The reaction mixture was concentrated in vacuo, the residue was solubilized in EtOAc, Et 2 O and H 2 O, the organic phase was washed with H 2 O, HCl and N 1 H 2 O, aq. of sat. NaHCO 3, brine H 2 O. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain 9-fluoro-6-methyl-1,3,4,5-tetrahydro-pyrido [4,3-b] tert-butyl ester. ] indole-2-carboxylic acid as an orange solid (0.23 g, 0.7 mmol).

Step Β. To a solution of 9-Fluoro-6-methyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.23 g, 0.7 mmol) in DME (3.9 mL) was added triturated KOH (0.19 g, 3.5 mmol) and Mel (0.98 g, 6.9 mmol) at 20 ° C. The reaction mixture was stirred at 85 ° C for 6h, cooled, diluted with H2O and extracted with Et2O. The combined organic solution was washed with H2O and brine and dried over MgSO4, filtered and concentrated in vacuo to give 9-fluoro-5,6-dimethyl-1,3,4,5-acid tert-butyl ester. tetrahydro-pyrido [4,3-b] indole-2-carboxylic in the form of a yellow oil. (0.21 g, 0.6 mmol).

Step C. To 9-Fluoro-5,6-dimethyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.21 g, 0 0.6 mmol) at 0 ° C was added 20% TFA / CH 2 Cl 2 (6.3 mL) and stirred for 10 min. Stirred at 20 ° C for an additional 1 h, concentrated in vacuo to a greenish brown solid (0.26 g, 0.7 mmol), of which 260.0 mg was purified by HPLC (Me-OH / H2 O) to obtaining the title compound (56.7 mg, 0.2 mmol): MS (ES) 252.98 (M + H). EXAMPLE 50

6-Chloro-8-fluoro-5,9-dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 82 </formula>

Step A. To a solution of 6-chloro-8-fluoro-9-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (0.2 g, 0, 7 mmol) and di-tert-butyl dicarbonate (0.17 g, 0.8 mmol) in 1,4-dioxane (6.9 mL) was added 1 N NaOH (2.2 mL, 2.2 mmol) ) at 20 ° C and stirred for 1 h. The reaction mixture was concentrated in vacuo, the residue was solubilized in EtOAc, Et2O and H2O, the organic phase was washed with H2O, 1N HCl, H2O, aq. NaHCO 3 sat., H 2 O and brine. The organic phase was dried over filtered MgSO4 and concentrated in vacuo to obtain 6-chloro-8-fluoro-9-methyl-1,3,4,5-tetrahydro-pyrido [4] tert-butyl ester. 1,3-b] indole-2-carboxylic acid as an orange solid (0.23g, 0.7 mmol).

Step Β. To a solution of 6-chloro-8-fluoro-9-methyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0.23 g 0.7 mmol) in DME (3.9 mL) was added triturated KOH (0.19 g, 3.5 mmol) and Mel (0.98 g, 6.9 mmol) at 20 ° C. The reaction mixture was stirred at 85 ° C for 6h, cooled, diluted with H2O and extracted with Et2O. The combined organic solution was washed with H 2 O and brine and dried over MgSO 4, filtered and concentrated in vacuo to obtain 6-chloro-8-fluoro-5,9-dimethyl-1 tert-butyl ester. 3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid as a yellow oil. (0.21 g, 0.6 mmol).

Step C. To 6-Chloro-8-fluoro-5,9-dimethyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (0, 21 g, 0.6 mmol) at 0 ° C was added 20% TFA / CH 2 Cl 2 (6.3 mL) and stirred for 10 min. Stirred for an additional 1 h at 20 ° C, concentrated in vacuo to a greenish brown solid (0.26 g, 0.7 mmol), of which 260.0 mg was purified by HPLC (MeOH / H2 O) to obtain the title compound ( 56.7 mg, 0.2 mmol):

MS (ES) 252.98 (M + H). EXAMPLE 51

7-Chloro-5-methyl-6- (methylthio) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole

<formula> formula see original document page 83 </formula>

Step A. 7-Chloro-6-methylsulfanyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (388 mg, 1.1 mmol) was prepared by following the procedures of example 49 Step A starting from 7-chloro-6-methylsulfanyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride (example 30,333 mg, 1.15 mmol ), di-butyl dicarbonate (280 mg, 1.27 mmol), 1 N Na-OH (3.5 mL, 3.5 mmol), 1,4-dioxane (11 mL). 7-Chloro-5-methyl-6-methylsulfanyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester (330 mg, 0.9 mmol ) was prepared by following the procedures of example 49 Step B starting from 7-chloro-6-methylsulfanyl-1,3,4,5-tetrahydro-pyrido [4,3-b] indole-2-carboxylic acid tert-butyl ester ( 370 mg, 1.05 mmol), Mel (1.55 g, 10.5 mmol), KOH (294 mg, 5.25 mmol) and DME (6.0 mL).

Step C. The title compound (213 mg, 0.8 mmol) was prepared following the procedures of example 49 Step C starting from 7-chloro-5-methyl-6-methylsulfanyl-1,3,4-acid tert-butyl ester, 5-Tetrahydro-pyrido [4,3-b] indol-2-carboxylic acid (330 mg, 0.9 mmol) and 20% TFA / CH 2 Cl 2 (8.0 mL) as a yellow solid: MS (ES) 267 0.1 (M + H).

While it is apparent that the patent application embodiments described herein are well-suited to meet the above objectives, it will be appreciated that various modifications and other embodiments may be implemented by those skilled in the art and it is intended that the appended claims cover all such modifications. and modalities that fit within the real spirit and scope of this pending request.

A number of references have been cited and the entire descriptions of which are incorporated herein by reference. REFERENCE LIST

Arnt1 J. Acta Pharmacol. et Toxicol. (1982) 51: 321-329. Berridge M.J., Downes P.C., Hanley M.R. (1982) Lithium amplifies agonist-dependent phosphotidyinositol response in brain and salivary giands. Biochem. J., 206: 587-595.

Costall, B and Nailor, RJ. Psychopharmacology. (1975) 43: 69-74.Egan C.T., Herrick-Davis K., Miller K., Glennon R.A. and Teitler M. (1998) Agonist activity of LSD and Iisuride at cloned 5-HT2a and 5-HT2C receptors. Psy-chopharmacology, 136: 409-414.

Fitzgerald LW, Conklin DS, Krause CM1 Marshall AP, Patterson JP, Tran DP, Lyer G, Kostich WA, Largent BL1 Hartig PR (1999) High-affinity agonist bin-ding correlates with efficacy (intrinsic activity) at the human serotonin 5- HT2Ae 5-HT2c receptors: evidence favoring the ternary complex and two-statemodels of agonist action. J. Neurochem., 72: 2127-2134.

Horlick, RA, Sperle, K., Breth, LA, Reid, CC, Shen, ES, Robbinds, AK, Cooke, GM, Largent, BL (1997) Rapid Generation of stable cell Iines by pressing corticotrophin-releasing receptor hormone for drug discovery. Protein in Expr. Purif. 9: 301-308.

Claims (10)

1. A compound or a pharmaceutically acceptable salt or a prodrug or a solvate or a stereoisomer thereof according to Formula I wherein R 1 is selected from the group consisting of H, C3-7 cycloalkyl, C1-3 alkylsubstituted with 0-3 R9, C2.4 alkenylsubstituted with 0-2 R9, C2.4 alkynylsubstituted with 0-2 R91 R2 and R3 are independently selected from the group consisting of H and C1-4 substituted alkyl with 0-3 R9 R4, R5, R6 and R7 are independently selected from the group consisting of H1 halo, -CF3, -OCF3, -OH1 -CN, -NO2, -OCH3, -SCH3, -SCF3, -CF2CF3, - OR12, -SR12, -NR12R131 -C (O) H, -C (O) R12, -NR14C (O) R12, -OC (O) R12, -OC (O) OR12, -S (O) R12, - S (O) 2R12, -S (O) NR12R13, -S (O) 2NR12R13, -NR14S (O) R12i-NR12C (O) R15, -NR12C (O) OR151 -NR12C (O) NHR15, C1-4 alkyl substituted with 0-2 R8, C2.6 substituted alkenyl with 0-2 R8, C2-6 substituted alkynyl with 0-2 R8, C3.6 substituted cycloalkyl with 0-2 R8 and C3. 0-3R33, wherein at least two of R4, R5, R6 and R7 are not H, optionally one of R4 and R5, R5 and R6 or R6 and R7 may be taken together to form a 5-10 membered carbocyclyl, a 5-10 membered heterocyclyl, a 5-7 membered aryl or a 5-7 membered heteroaryl ring; R8 is selected from the group consisting of halo, -CF3, -OCF3, -OH, -CN, -NO2, -CF 2 CF 3, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl; s-butyl, t-butyl, -OR 12, -SR 12, -NR 12 R 13, -C (O) H, -C (O) R 12, -C (O) NR 12 R 13, -NR 14 C (O) R 12, -C (O) OR12, -OC (O) R12, -OC (O) OR12, -S (O) R12, -S (O) 2R12, -S (O) NR12R131 -S (O) 2NR12R131 -NR14S (O) R12, - NR14S (O) 2R12, -NR12G (O) R15, -NR12C (O) OR15, -NR12S (O) 2R15, -NR12C (O) NHR15, phenyl substituted with 0-5 R33, C3-10-substituted carbocyclic 0-3 R331 and 5-10 membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N1 O, and S substituted with 0-3 R33; R9 is selected from the group consisting of halo, - C 1-3 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2,4 alkynyl, C 3-6 cycloalkyl, R 12 is selected from the group consisting of H, C 1-6 substituted alkyl with O- 2 R12a, C2.6 substituted alkenyl with 0-2 R12a, C2.6 substituted alkynyl with 0-2 R12a, C3.6 substituted cycloalkyl with 0-3 R331 substituted aryl with 0-5 R331 C3.10 substituted carbocyclyl with 0- 3 R33 and 5-10 membered heterocyclic ring system with having from 1-4 heteroatoms selected from the group consisting of N1 O, and S substituted with 0-3 R33, R12a is selected from the group consisting of H, halo, -OH, -CN, -NO2, -CO2H, -SO2R45, -SOR45, -SR45, -NR46SO2R45, -NR46COR45, -NR46R47, -SO2NR46R46, -CONR46R46, -OR45, = 0, Cv4 alkyl, C2.6 alkenyl, C2.6 alkylene, phenyl substituted with 0-5 R33, C3.10 0-3 R33-substituted carbocyclyl, 5-10 membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3R33; R13 is selected from the group consisting of H, C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl, optionally R 12 and R 13 may be taken together to form a 5-6 membered level optionally substituted with -O- or -N ( Optionally R12 and R13 may be taken together to form a 9-10 membered bicyclic heterocyclic ring system containing 1-3 heteroatoms selected from the group consisting of N, O and S wherein si Bicyclic heterocyclic deanel may be saturated, partially saturated or unsaturated and the bicyclic heterocyclic ring system is substituted with 0-3 R16; R14 is selected from the group consisting of H and C1-4 alkyl; R15 is selected from the group consisting of C1-4 alkyl, C2.4 alkenyl and C2.4 alkynyl, R16, at each occurrence, is independently selected from Η, OH, halo, CN, NO2, CF3, SO2R451 NR46R47 -C (= O) H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-3 haloalkyloxy and C 1-3 alkyloxy; R 33 is selected from the group consisting of H1 OH, halo, -CN1-NO2, -CF3, -OCF3 -SO2R451 -S (O) R451 -SR451 -NR46R471 -NHC (O) R45, -C (O) NR46R461 -C (O) H1 -C (O) R451- C (O) OR451 -OC (O) R451 -OR451 C1-6 alkyl, C2.6 alkenyl, C2-6 alkynyl, C1 haloalkyl, C1-4 alkoxy, C1-4 haloalkyloxy, C3-6 cycloalkyl, phenyl, aryl substituted with 0-2 R341 C1-2 alkyl substituted with 0-2 R34 and C2-6 alkenyl substituted with 0-2 R34; R34, at each occurrence, is independently selected from OH1 C-maloxy, -SO2 R45, -NR46 R471 NR46 R46C (O ) -, and (C1-4 alkyl) CO2-; R45 is C1-4 alkyl; R46, at each occurrence, is independently selected from H and C1-4 alkyl; R47, at each occurrence, is ind independently selected from H, C-malkyl, -C (0) NH (C 1-4 alkyl), -SO 2 (C 1-4 alkyl), -C (O) 0 (C 1-4 alkyl), -C (0) ( C1.4 alkyl) and -C (O) H. A compound according to claim 1, wherein R 4, R 5, R 6 and R 7 are independently selected from the group consisting of H, halo, -CF 31 -OCF 3 -CN 1 -OCH 31 -SCH 3, -SCF 3, -CF 2 CF 3, -OR 12, SR12, -NR12R13, -C (O) R12, C1-2 alkyl substituted with 0-2 R8 and C3-6 cycloalkyl substituted with 0-2R8, wherein at least two of R4, R51 R6 and R7 are not H, optionally one of R4 and R5, R5 and R6 or R6 and R7 may be taken together to form a 5-10 membered carbocyclyl, a 5-7 membered aryl ring or a 5-7 membered heteroaryl ring. A compound according to claim 2, wherein R2 is H. A compound according to claim 3 wherein R 1 is H. A compound according to claim 4, wherein R 3 is H. A compound according to claim 1, wherein the compound is: 6,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 6,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 6,7-dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride; 7,9-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 6,9-Dichloro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 6,7-Dichloro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 6,8-Difluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 7,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 8,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 7,9-Dichloro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 9-Fluoro-6-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 9-Chloro-6-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 8-Methoxy-6-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 7-Chloro-6-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 7-Chloro-6-fluoro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride; 6-Bromo-9-fluoro-6-methyl-2,3,4,5-tetrahydro-1'-pyrido [4,3-b] indole; 6-Bromo-9-chloro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride; 6-Chloro-9-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 8-Bromo-6-iodo-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride; 6-Chloro-9- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 8-Fluoro-6- (trifluoromethyl) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole; 8-Methyl-6- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 8-Methoxy-6- (trifluoromethyl) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole; 6-Chloro-8- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 9-Methyl-6- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 6-Methyl-7- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 8-Bromo-6-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 9-Chloro-6-methylsulfanyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 6-Methylsulfanyl-9-trifluoromethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride; 7-Chloro-6-methylsulfanyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 7-Bromo-6- (3-chloropropylthio) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 6- (3-Chloropropylthio) -9-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; -7-Chloro-6- (3-chloropropylthio) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 9-Bromo-6- (3-chloropropylthio) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride 6- (3-chloropropylthio) -9 hydrochloride nitro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 8-methoxy-6-nitro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole; 6-Bromo-9-nitro-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole; 7-Chloro-6- (p-tolylthio) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 6- (4-Chlorophenylthio) -9- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 9-Chloro-6- (4-chlorophenylthio) -2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole hydrochloride 7-Methyl-6- (p- tolylthio) -2,3,4,5-tetrahydro-1H-pyrido {4,3-b] indole; 8-Bromo-9-chloro-6-methyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole; -6-Chloro-8-fluoro-9-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; -6,8,9-Trichloro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole hydrochloride; 6,7-Dichloro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 5,6,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 9 - Chloro-5,6-dimethyl-2,3,4,5-tetrahydro-1 H -pyrido [4,3-b] indole; 5,7,9-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 9-Fluoro-5,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 6-Chloro-8-fluoro-5,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and 7-Chloro-5-methyl-6- (methylthio) --2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole. A pharmaceutical composition, comprising: at least one compound as defined in claim 1, and at least one pharmaceutically acceptable carrier or diluent. A pharmaceutical composition according to claim 7 which further comprises: at least one additional therapeutic agent. 9. Process for treating various diseases, health conditions and disorders such as, for example, metabolic disorders, including but not limited to obesity, diabetes, diabetic complications, arteriosclerosis, impaired glucose tolerance and dyslipidemia; central nervous system disorders including, but not limited to, anxiety, depression, obsessive compulsive disorder, panic disorder, psychosis, schizophrenia, sleep disorders, sexual disorders, and social phobias; migraine and gastrointestinal disorders upon administration to a mammal require such treatment of a therapeutically effective amount of a novel compound as defined in claim 1. A process according to claim 9, wherein the disease, state of health or disorder is obesity.